CN101018780B

CN101018780B - Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors

Info

Publication number: CN101018780B
Application number: CN200580030636XA
Authority: CN
Inventors: J·J·崔; L·A·芬克; 贾磊; 龚蓓蓓; J·J·蒙; M·D·纳姆布; M·A·佩里施; 沈洪; M·B·特兰-杜比
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd; Pfizer Inc
Priority date: 2004-08-26
Filing date: 2005-08-15
Publication date: 2012-01-11
Anticipated expiration: 2025-08-15
Also published as: AP2332A; CY1111138T1; EP1784396B8; AR050529A1; AU2005276132B2; GT200500226A; WO2006021881A2; PT1784396E; EA011725B1; CR20120421A; NO20071320L; SI1784396T1; SV2006002208A; WO2006021881A3; ATE492544T1; US20060128724A1; BRPI0514537B8; DE602005025499D1; MX2007002310A; JP4167295B2

Abstract

Compounds of formula (1) are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.

Description

As the substituted aminoheteroaryl compounds of the pyrazoles of kinases inhibitor

Technical field

Generally speaking, the present invention relates to novel chemical compound and method.More specific, the present invention provides novel pyrazoles substituted aminoheteroaryl compounds, particularly aminopyridines and amino pyrazine class, and it has protein hydroxyphenylaminopropionic acid kinase activity, and method synthetic and this compounds of use.Preferred compound is for can be used for treating the c-Met suppressor factor of abnormal cell growth (for example cancer).

Background technology

Shown that pHGF (HGF) acceptor (c-MET or HGFR) receptor tyrosine kinase (RTK) participates in tumour and generate in many human cancers, have the tumour progression of enhanced cell mobility and intrusion, and transfer (has been consulted; Ma for example, P.C., Maulik; G., Christensen, J.&Salgia; R. (2003b) .CancerMetastasis Rev, 22,309-25; Maulik, G., Shrikhande, A., Kijima, T., Ma, P.C., Morrison, P.T.&Salgia, R. (2002b) .CytokineGrowthFactorRev, 13,41-59).C-MET (HGFR) can comprise small cell lung cancer (SCLC) in various human cancers, via over-expresses or sudden change and be activated (Ma, P.C., Kijima; T., Maulik, G., Fox, E.A.; Sattler, M., Griffin, J.D., Johnson; B.E.&Salgia, R. (2003a) .CancerRes, 63,6272-6281).

C-MET is a receptor tyrosine kinase, and it is by Met proto-oncogene coding, and the biological action of transduction pHGF (HGF), and this factor also is called as spreading factor (SF).People such as Jiang, Crit.Rev.Oncol.Hematol.29:209-248 (1999).C-MET and HGF express in many tissues, although their expression mainly is limited to respectively in the cell in epithelium and mesenchyme source usually.C-MET and HGF are that the normal mammalian growth is required, and have shown that its body at cell migration, hyperplasia and survival, form generation differentiation and 3-dimension tubular structure (for example kidney duct cell, gland formation etc.) is important in forming.Except its to the epithelial effect, reported that HGF/SF is a kind of angiogenesis factor, and the c-MET signal in the endotheliocyte can bring out the necessary many cellular response of vasculogenesis (hyperplasia, mobility, intrusion).

Shown that the c-MET acceptor is expressed in many human cancers.Also shown c-Met and part HGF thereof under high level coexpression in multiple human cancer (particularly sarcoma).But,, regulate so the c-MET signal the most often interacts through tumour-matrix (tumour-host) because this acceptor is often expressed through different cell types with part.Have again, in the subclass of human cancer, observed the c-MET gene and amplified, suddenly change and reset.Family with the kinase whose germ line mutation of activation c-MET is prone to suffer from multiple tumor of kidney, and the tumour in other tissue.Many researchs have made the expression of c-MET and/or HGF/SF produce related with the PD state of dissimilar cancers (comprising lung, colon, breast, prostate gland, liver, pancreas, brain, kidney, ovary, stomach, skin and osteocarcinoma).Have again, shown that the over-expresses of c-MET or HGF is relevant with the disease consequence that poor prognosis reaches in many main human cancers (comprising lungs, liver, stomach and mastocarcinoma).C-MET also directly involves the cancer of no successful regimen, for example pancreas cancer, neurospongioma and hepatocellular carcinoma.

C-MET (HGFR) suppressor factor, its synthetic instance that reaches purposes; Can consult the u.s. patent application serial number of submitting on February 26th, 2,004 10/786; 610; Its title is " as the aminoheteroaryl compounds of kinases inhibitor ", and the corresponding International Application PCT/US2004/005495 of the same title of submitting on February 26th, 2004, and it is for reference that its disclosure is all incorporated this paper into it in full.

Expectation has novel c-MET (HGFR) suppressor factor, and the method for using this type of inhibitor for treating abnormal cell growth (for example cancer).

Summary of the invention

In one embodiment, the present invention provides formula 1Compound or its pharmacy acceptable salt, hydrate or solvate,

Wherein:

Y is N or CR ¹²

A is C _6-12Aryl, 5-12 unit heteroaryl, C _3-12Naphthenic base or 3-12 unit are assorted alicyclic, and A is optional by one or more R ³Group replaces;

R ¹Be selected from

Optional by one, two or three R ¹³Group replaces;

R ²Be hydrogen, halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵, and R ²In each hydrogen optional by R ⁸Replace;

Each R ³Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nNR ⁴R ⁵,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nOR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵, R ³In each hydrogen optional by R ⁸Replace, and the R on the adjacent atom ³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12The assorted alicyclic group of naphthenic base or 3-12 unit;

Each R ⁴, R ⁵, R ⁶And R ⁷Independent is hydrogen, halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Aryl, assorted alicyclic, the first heteroaryl of 5-12 of 3-12 unit; Or be bonded to the R on the identical nitrogen-atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge with its bonded nitrogen, forming 3 to 12 yuan of assorted alicyclic or first heteroaryls of 5-12, it is optional to contain 1 to 3 other heteroatoms that is selected from N, O and S; Or be bonded to the R on the identical carbon atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge and form C _3-12Naphthenic base, C _6-12Aryl, the assorted alicyclic or first heteroaryl of 5-12 of 3-12 unit; And R ⁴, R ⁵, R ⁶And R ⁷In each hydrogen optional by R ⁸Replace, or at R ⁴, R ⁵, R ⁶And two Wasserstoffatomss on the identical carbon atoms are optional among the R7 is oxo (oxo) substituting group;

Each R ⁸Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-NH ₂,-CN ,-OH ,-O-C _1-12Alkyl ,-O-(CH ₂) _nC _3-12Naphthenic base ,-O-(CH ₂) _nC _6-12Aryl ,-O-(CH ₂) _n(3-12 unit assorted alicyclic) or-O-(CH ₂) _n(5-12 unit heteroaryl); And R ⁸In each hydrogen optional by R ¹¹Replace;

Each R ⁹With R ¹⁰Independent is hydrogen, halogen, C _1-12Alkyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵R ⁹Or R ¹⁰Can merge to form C with the annular atoms of A or the substituting group of A _3-12Naphthenic base, assorted alicyclic, the C of 3-12 unit _6-12Aryl or be fused to the 5-12 unit heteroaryl ring of A; And R ⁹With R ¹⁰In each hydrogen optional by R ³Replace;

Each R ¹¹Independent is halogen, C _1-12Alkyl, C _1-12Alkoxyl group, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-O-C _1-12Alkyl ,-O-(CH ₂) _nC _3-12Naphthenic base ,-O-(CH ₂) _nC _6-12Aryl ,-O-(CH ₂) _n(3-12 unit is assorted alicyclic) ,-O-(CH ₂) _n(5-12 unit heteroaryl) or-CN, and R ¹¹In each hydrogen optional by halogen ,-OH ,-CN, can-C halogenated by partially or completely _1-12Alkyl, can-O-C halogenated by partially or completely _1-12Alkyl ,-CO ,-SO or-SO ₂Replace;

R ¹²Be hydrogen, halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵, and R ¹²In each hydrogen optional by R ³Replace;

Each R ¹³Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵,-C (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _n(3-12 unit is assorted alicyclic) ,-(CR ⁶R ⁷) _n(C _3-12Naphthenic base) ,-(CR ⁶R ⁷) _n(C _6-12Aryl) ,-(CR ⁶R ⁷) _n(5-12 unit heteroaryl) ,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵Or-(CR ⁶R ⁷) _nC (O) R ⁴, the R on the adjacent atom ¹³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12The assorted alicyclic group of naphthenic base or 3-12 unit, and R ¹³In each hydrogen optional by R ³Replace;

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

T is 1,2,3 or 4, and

Each p independently is 1 or 2;

Condition is; This compound is not that [1-(2 for 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1H-pyrazoles-4-yl)-pyridine-2-base amine, [1-(2 for 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2-tetramethyleneimine-1-base-ethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine, [1-(2 for 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2-diisopropylaminoethyl-ethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine, [1-(2 for 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2-morpholine-4-base-ethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine or 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridine-2-base amine.

In the particular aspects of this embodiment, each R ³Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nNR ⁴R ⁵,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nOR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵, R ³In each hydrogen optional by R ⁸Replace, and the R on the adjacent atom ³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12The assorted alicyclic group of naphthenic base or 3-12 unit; And

Each R ⁴, R ⁵, R ⁶And R ⁷Independent is hydrogen, halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Aryl, assorted alicyclic, the first heteroaryl of 5-12 of 3-12 unit; Or be bonded to the R on the identical nitrogen-atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge with its bonded nitrogen, forming 3 to 12 yuan of assorted alicyclic or first heteroaryls of 5-12, it is optional to contain 1 to 3 other heteroatoms that is selected from N, O and S; Or be bonded to the R of identical carbon atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge and form C _3-12Naphthenic base, C _6-12Aryl, the assorted alicyclic or first heteroaryl of 5-12 of 3-12 unit; And R ⁴, R ⁵, R ⁶And R ⁷In each hydrogen optional by R ⁸Replace.

In the particular aspects of this embodiment, A is C _6-12Aryl or 5-12 unit heteroaryl, optional by one or more R ³Group replaces.

In another particular aspects of this embodiment, and to make up any other be not inconsistent particular aspects, and A is a phenyl, by one, two or three R ³Group replaces, and is preferably one, two or three halogen.

In another particular aspects of this embodiment, and to make up any other be not inconsistent particular aspects, and t is 1, R ⁹Be methyl, and R ¹⁰Be hydrogen.

In another particular aspects of this embodiment, and to make up any other be not inconsistent particular aspects, and Y is N, and R ²Be hydrogen.

In another particular aspects of this embodiment, and to make up any other be not inconsistent particular aspects, and Y is CR ¹², R ²Be hydrogen, and R ¹²Be hydrogen.

In another particular aspects of this embodiment, and to make up any other be not inconsistent particular aspects, and t is 1, R ¹⁰Be hydrogen, and R ⁹Merge with the annular atoms of A, be fused to the C of A with formation _3-12Cycloalkyl ring.

In another embodiment, the present invention provides compound or its pharmacy acceptable salt, hydrate or the solvate of formula 2,3 or 4,

Wherein:

Y is N or CR ¹²

A is C _6-12Aryl, 5-12 unit heteroaryl, C _3-12Alkyl or 3-12 unit are assorted alicyclic, and A is optional by one or more R3 groups replacements;

Each R ⁴, R ⁵, R ⁶And R ⁷Independent is hydrogen, halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Aryl, assorted alicyclic, the first heteroaryl of 5-12 of 3-12 unit; Or be bonded to the R on the identical nitrogen-atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge with its bonded nitrogen, forming 3 to 12 yuan of assorted alicyclic or first heteroaryls of 5-12, it is optional to contain 1 to 3 other heteroatoms that is selected from N, O and S; Or be bonded to the R on the identical carbon atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge and form C _3-12Naphthenic base, C _6-12Aryl, the assorted alicyclic or first heteroaryl of 5-12 of 3-12 unit; And R ⁴, R ⁵, R ⁶And R ⁷In each hydrogen optional by R ⁸Replace, or at R ⁴, R ⁵, R ⁶And R ⁷Two Wasserstoffatomss on the middle identical carbon atoms are optional to be the oxo substituting group;

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

T is 1,2,3 or 4, and

Each p independently is 1 or 2;

Each R ⁴, R ⁵, R ⁶And R ⁷Independent is hydrogen, halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Aryl, assorted alicyclic, the first heteroaryl of 5-12 of 3-12 unit; Or be bonded to the R on the identical nitrogen-atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge with its bonded nitrogen, forming 3 to 12 yuan of assorted alicyclic or first heteroaryls of 5-12, it is optional to contain 1 to 3 other heteroatoms that is selected from N, O and S; Or be bonded to the R on the identical carbon atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge and form C _3-12Naphthenic base, C _6-12Aryl, the assorted alicyclic or first heteroaryl of 5-12 of 3-12 unit; And R ⁴, R ⁵, R ⁶And R ⁷In each hydrogen optional by R ⁸Replace.

In another particular aspects of this embodiment, and to make up any other be not inconsistent particular aspects, and t is 1, R ¹⁰Be hydrogen, and R ⁹Merge the C that is fused to A with formation with the annular atoms of A _3-12Cycloalkyl ring.

In another embodiment, the present invention provides formula 2aCompound or its pharmacy acceptable salt, hydrate or solvate,

Wherein:

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

Each p independently is 1 or 2.

At the particular aspects of this embodiment, R ²Be hydrogen.

In another embodiment, the present invention provides formula 2bCompound or its pharmacy acceptable salt, hydrate or solvate,

Wherein:

Each R ³Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nNR ⁴R ⁵,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nOR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵, R ³In each hydrogen optional by R ⁸Replace, and the R on the adjacent atom ³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12Naphthenic base or 3-12 unit are assorted alicyclic;

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

Each p independently is 1 or 2;

Condition is; This compound is not that [1-(2 for 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1H-pyrazoles-4-yl)-pyridine-2-base amine, [1-(2 for 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2-tetramethyleneimine-1-base-ethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine, [1-(2 for 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-(2-diisopropylaminoethyl-ethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine, [1-(2 for 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2-morpholine-4-base-ethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine or 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridine-2-base amine.

At the particular aspects of this embodiment, R ²Be hydrogen.

At another particular aspects of this embodiment, R ¹²Be hydrogen.

At another particular aspects of this embodiment, R ²With R ¹²Be hydrogen.

In another embodiment, the present invention provides formula 3aCompound or its pharmacy acceptable salt, hydrate or solvate

Wherein:

Each R ¹³Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵,-C (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _n(3-12 unit is assorted alicyclic) ,-(CR ⁶R ⁷) _n(C _3-12Naphthenic base) ,-(CR ⁶R ⁷) _n(C _6-12Aryl) ,-(CR ⁶R ⁷) _n(5-12 unit heteroaryl) ,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵Or-(CR ⁶R ⁷) _nC (O) R ⁴, the R on the adjacent atom ¹³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12Naphthenic base or 3-12 unit are assorted alicyclic, and R ¹³In each hydrogen optional by R ³Replace;

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

Each p independently is 1 or 2.

In the particular aspects of this embodiment, each R ³Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nNR ⁴R ⁵,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nOR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵, R ³In each hydrogen optional by R ⁸Replace, and the R on the adjacent atom ³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12Naphthenic base or 3-12 unit are assorted alicyclic; And

At the particular aspects of this embodiment, R ²Be hydrogen.

In another embodiment, the present invention provides formula 3bCompound or its pharmacy acceptable salt, hydrate or solvate

Wherein:

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

Each p independently is 1 or 2.

Each R ⁴, R ⁵, R ⁶And R ⁷Independent is hydrogen, halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Aryl, assorted alicyclic, the first heteroaryl of 5-12 of 3-12 unit; Or be bonded to the R on the identical nitrogen-atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge with its bonded nitrogen, forming 3 to 12 yuan of assorted alicyclic or first heteroaryls of 5-12, it is optional to contain 1 to 3 other heteroatoms that is selected from N, O and S; Or any two R that are bonded on the identical carbon atoms ⁴, R ⁵, R ⁶And R ⁷In any two can merge and form C _3-12Naphthenic base, C _6-12Aryl, the assorted alicyclic or first heteroaryl of 5-12 of 3-12 unit; And R ⁴, R ⁵, R ⁶And R ⁷In each hydrogen optional by R ⁸Replace.

At the particular aspects of this embodiment, R ²Be hydrogen.

At another particular aspects of this embodiment, R ¹²Be hydrogen.

At another particular aspects of this embodiment, R ²With R ¹²Be hydrogen.

In another embodiment, the present invention provides formula 4aCompound or its pharmacy acceptable salt, hydrate or solvate

Wherein:

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

Each p independently is 1 or 2.

At the particular aspects of this embodiment, R ²Be hydrogen.

In another embodiment, the present invention provides formula 4bCompound or its pharmacy acceptable salt, hydrate or solvate

Wherein:

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

Each p independently is 1 or 2.

In the particular aspects of this embodiment, each R ³Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nNR ⁴R ⁵,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nOR ⁴,-NR ⁴C (O) R ⁵-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵, R ³In each hydrogen optional by R ⁸Replace, and the R on the adjacent atom ³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12The assorted alicyclic group of naphthenic base or 3-12 unit; And

At the particular aspects of this embodiment, R ²Be hydrogen.

At another particular aspects of this embodiment, R ¹²Be hydrogen.

At another particular aspects of this embodiment, R ²With R ¹²Be hydrogen.

In another embodiment, the present invention provides formula 5aCompound or its pharmacy acceptable salt, hydrate or solvate

Wherein:

Each R ³Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nNR ⁴R ⁵,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nOR ⁴,-O (CR ⁶R ⁷) _nR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵, R ³In each hydrogen optional by R ⁸Replace, and the R on the adjacent atom ³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12The assorted alicyclic group of naphthenic base or 3-12 unit;

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

Each p independently is 1 or 2.

In another embodiment, the present invention provides formula 5bCompound or its pharmacy acceptable salt, hydrate or solvate

Wherein:

R ³Be halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-(CR ⁶R ⁷) _nOR ⁴,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nNR ⁴R ⁵,-O (CR ⁶R ⁷) (CR ⁶R ⁷) _nOR ⁴,-O (CR ⁶R ⁷) _nR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-(CR ⁶R ⁷) _nNCR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵Or-C (O) NR ⁴R ⁵, R ³In each hydrogen optional by R ⁸Replace, and the R on the adjacent atom ³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12The assorted alicyclic group of naphthenic base or 3-12 unit;

Each R ⁸Independent is halogen, C _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Assorted alicyclic, the first heteroaryl of 5-12 of aryl, 3-12 unit ,-NH ₂,-CN ,-OH ,-O-C1-1 ₂Alkyl ,-O-(CH ₂) _nC _3-12Naphthenic base ,-O-(CH ₂) _nC _6-12Aryl ,-O-(CH ₂) _n(3-12 unit assorted alicyclic) or-O-(CH ₂) _n(5-12 unit heteroaryl); And R ⁸In each hydrogen optional by R ¹¹Replace;

Each m independently is 0,1 or 2;

Each n independently is 0,1,2,3 or 4;

Each p independently is 1 or 2.

In another embodiment, the present invention provides compound, and it is selected from the group of being made up of following compound:

Or its pharmacy acceptable salt, solvate or hydrate.

Or its pharmacy acceptable salt, solvate or hydrate.

Or its pharmacy acceptable salt, solvate or hydrate.

Or its pharmacy acceptable salt, solvate or hydrate.

Or its pharmacy acceptable salt, solvate or hydrate.

Or its pharmacy acceptable salt, hydrate or solvate.

Or its pharmacy acceptable salt, hydrate or solvate.

Or its pharmacy acceptable salt, hydrate or solvate.

Or its pharmacy acceptable salt, hydrate or solvate.

Or its pharmacy acceptable salt, hydrate or solvate.

In another embodiment, the present invention provides a kind of pharmaceutical composition, and it comprises any compound of the present invention, and pharmaceutically acceptable carrier.The case description of this kind compsn is in hereinafter.

Preferred compound of the present invention comprises having as passing through IC ₅₀, Ki or suppress any one or more defined c-MET inhibition of per-cent (%I) active those.Those skilled in the art can measure a kind of compound and whether have this kind activity easily through carrying out suitable detection, and the explanation of this kind detection is shown in this paper embodiment part.In one embodiment, preferred especially compound has and is lower than 5 μ M, or is lower than 2 μ M, or is lower than 1 μ M, or is lower than 500nM or is lower than 200nM or is lower than the c-MET Ki of 100nM.In another embodiment, the c-MET of preferred especially compound under 1 μ M suppresses to be at least 10% or at least 20% or at least 30% or at least 40% or at least 50% or at least 60% or at least 70% or at least 80% or at least 90%.Measuring the active method of c-MET/HGFR is described among this paper embodiment.

In another embodiment, the method that the present invention provides a kind of treatment to comprise abnormal cell growth in the human Mammals, this method comprise and give this Mammals any pharmaceutical composition of the present invention.

In the particular embodiment of the inventive method described in any this paper; Abnormal cell growth is a cancer, includes but not limited to one or more the combination in vegetation, primary CNS lymphoma, spinal column axis tumour, brain stem neurospongioma, pituitary adenoma or the aforementioned cancer of the sarcoma, urethral carcinoma, penile cancer, prostate cancer of cancer, cancer of the stomach, colorectal carcinoma, breast cancer, uterus carcinoma, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, carcinoma vulvae, Huo Qijin (Hodgkin) family name disease, esophagus cancer, the carcinoma of small intestine of cancer, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, the anal regions of lung cancer, osteocarcinoma, pancreas cancer, skin carcinoma, head or neck, the cancer of endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, carcinoma of renal pelvis, cns (CNS).In another embodiment of this method, this abnormal cell growth is a benign proliferative diseases, includes but not limited to psoriasis, benign prostatauxe or restenosis.

In another embodiment, the present invention provides the method for HGFR disorder mediated in treatment Mammals (comprising the mankind), and this method comprises and gives any pharmaceutical composition of the present invention to this Mammals.

In the further particular embodiment of the inventive method described in any this paper; This method comprises that further giving a certain amount of one or more to this Mammals is selected from the material of antineoplastic agent, anti-angiogenic agent, signal transduction inhibitor and anti-proliferative agent, and said amount is effectively treated this abnormal cell growth altogether.This type material is included in PCT publication WO00/38715, WO00/38716, WO00/38717; WO00/38718, WO00/38719, WO00/38730; WO00/38665, among WO00/37107 and the WO00/38786 disclosed those, it is for reference that its disclosure is all incorporated this paper into it in full.

The instance of antineoplastic agent comprises mitotic inhibitor, for example vinca alkaloids verivate, for example vinealeucoblastine(VLB) vinorelbine, vindesine and vincristine(VCR); NSC-757., other NSC-757. (allochochine), Harry chrondroitin (halichondrine), N-benzoyl-trimethylammonium-methyl ether colchicinic acid, dolastatin 10, NSC-153858 (maystansine), WF 1360 (rhizoxin); Taxanes; For example taxol (paclitaxel), docetaxel (Taxotere), 2 '-N-[3-(dimethylamino) propyl group] glutarate (glutaramate) (D51-7059), his mycin (mitamycin) of thio-colchicine (thiocholchicine), trityl halfcystine, teniposide, methotrexate, azathioprine, Fluracil, cytosine arabinoside, 2 ' 2 '-difluoro Deoxyribose cytidine (gemcitabine), Dx and rice.Alkylating agent; For example cis-platinum, carboplatin, oxaliplatin (oxiplatin), NSC 256927, the N-ethanoyl-leucic ethyl ester of DL-sarcosyl-L-(Asaley or Asalex), 1; 4-cyclohexadiene-1; 4-diamino acid, 2; Two (the 1-'-aziridinos)-3 of 5-; 6-dioxo-diethyl ester (NSC-182986), 1; Acyl mustard (spirohydantoin mustard), teroxirone, four platinum, plug are for group, Tretamine, uracil mustard, two (3-methane sulfonyl oxygen base propyl group) amine hydrochlorate, MTC in general (hepsulfam), ametycin, hycanthone MTC (hycantheonemitomycin) C, mitoxolamide (mitozolamide), 1-(2-chloroethyl)-4-(3-chloro propyl group)-piperazine dihydrochloride, piperazinedione, pipobroman, porfiromycin, the spiral shell second of reviving in two (methanesulfonyloxy group) butane (two sulphur all (bisulfan) or bright sulphur all (leucosulfan)) of 4-, SC-178248, the U.S. pine of clo (clomesone), cyanic acid morpholinyl Dx, ring Dai Song (cyclodisone), NSC-132313, fluorodopan (fluorodopan), heptan; Nitrosoureas; For example cyclohexyl-chlorethylnitrosourea, methylcyclohexyl-chlorethylnitrosourea, 1-(2-chloroethyl)-3-(2; 6-dioxo-3-piperidyl)-and 1-nitroso-group-urea, two (2-chloroethyl) nitrosourea, Procarbazine, reach carbohydrazide, mustargen related compound, for example mustargen, endoxan, ifosfamide, melphalan, TV, estramustine phosphate sodium, Shi Putuo sit because of (strptozoin) and TM.The DNA metabolic antagonist; For example 5 FU 5 fluorouracil, cytosine arabinoside, hydroxyurea, 2-[(3-hydroxyl-2-pyridyl (pyrinodinyl)) methylene radical]-hydrazine thiocarboxamide, deoxidation fluridine, 5-hydroxyl-2-formyl radical pyridine thiosemicarbazone, α-2 '-deoxidation-6-sulfo-guanosine, NSC-234714 glycinate, 5-azepine Deoxyribose cytidine, β-thioguanine dezyribonucleoside, cyclotidine, guanazole, inosine hydroxyl oxalic dialdehyde (glycodialdehyde), Mai Beixin (macbecin) II, pyrazoles imidazoles, CldAdo, pentostatin, Tioguanine, purinethol, bleomycin, 2-chlorodeoxyadenosine; The suppressor factor of thymidylate synthase, but the for example auspicious Qu Saiyu training U.S.A that replaces urges song plug farad shore, disodium Lip river (clofarabine), floxuridine and Fu Dala shore.The DNA/RNA metabolic antagonist; For example L-alanosine, 5-azacytidine, U 42126, aminopterin and verivate thereof; N-[2-chloro-5-[[(2 for example; 4-diamino--5-methyl-6-quinazolyl) methyl] amino] benzoyl-]-the L-aspartic acid, [4-[[(2 for N-; 4-diamino--5-ethyl-6-quinazolyl) methyl] amino] benzoyl-]-L-aspartic acid, N-[2-chloro-4-[[(2; 4-diamino-pteridyl) methyl] amino] benzoyl-]-L-aspartic acid, solubility BakerShi peace is for not (antifol), two chlorallyl 2 hydroxy 1,4 naphthoquinone (lawsone)s, brequinar, Tegafur (ftoraf), dihydro-5-azacytidine, methotrexate, N-(phosphonate group ethanoyl)-L-aspartic acid tetra-na salt, pyrazolo furans, trimetrexate, Plicamycin, dactinomycin, latent algae plain (cryptophycin) and analogue, for example latent algae plain-52; Or for example be disclosed in one of preferred metabolic antagonist in No. the 239362nd, the european patent application, for example N-(5-[ N-(3,4-dihydro-2-methyl-4-oxo viper azoles quinoline-6-ylmethyl)- N-methylamino-]-the 2-Thenoyl)-L-L-glutamic acid; Growth factor receptor inhibitors; The cell cycle suppressor factor; Imbedibility microbiotic, for example Zorubicin and bleomycin; Protein-based, Interferon, rabbit for example; And anti--hormones, for example anti-estrogens, for example Nolvadex ^TM(tamoxifen), or for example anti-androgens, for example Casodex ^TM(4 '-cyanic acid-3-(4-fluorophenyl alkylsulfonyl)-2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide).The single one-tenth that this kind mutual association treatment can be through simultaneously, take treatment in succession or separately assigns to reach.

Anti-angiogenic agent comprises MMP-2 (matrix metalloproteinase 2) suppressor factor, MMP-9 (matrix metalloproteinase 9) suppressor factor and COX-II (cyclo-oxygenase II) suppressor factor.The instance of spendable COX-II suppressor factor comprises CELEBREX ^TMA Laikao former times (alecoxib), valdecoxib and rofecoxib.The case description that can use NMPI is at WO96/33172 (on October 24th, 1996 openly), WO96/27583 (on March 7th, 1996 is open), No. the 97304971.1st, european patent application (on July 8th, 1997 filed an application); No. the 99308617.2nd, european patent application (on October 29th, 1999 filed an application), WO98/07697 (on February 26th, 1998 is open), WO98/03516 (on January 29th, 1998 is open); WO98/34918 (on August 13rd, 1998 is open), WO98/34915 (on August 13rd, 1998 is open), WO98/33768 (on August 6th, 1998 is open); WO98/30566 (on July 16th, 1998 is open), European patent disclose 606,046 (on July 13rd, 1994 is open); European patent discloses 931,788 (on July 28th, 1999 is open), WO90/05719 (May 31 nineteen ninety is open); WO99/52910 (on October 21st, 1999 is open), WO99/52889 (on October 21st, 1999 is open), WO99/29667 (on June 17th, 1999 is open); PCT International Application PCT/IB98/01113 (on July 21st, 1998 filed an application), No. the 99302232.1st, european patent application (on March 25th, 1999 filed an application), No. the 9912961.1st, British Patent Application (on June 3rd, 1999 filed an application); No. the 60/148th, 464, U.S. Provisional Application (on August 12nd, 1999 filed an application), USP 5; 863,949 (on January 26th, 1999 was given), USP 5; 861; 510 (on January 19th, 1999 was given) and European patent disclose 780,386 (on June 25th, 1997 is open), and it is for reference that it all incorporates this paper into it in full.Preferred L MP-2 and MMP-9 suppressor factor be have few or unrestraint MMP-1 active those.Be more preferably with respect to other matrix metalloproteinase (meaning is MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13), optionally suppress those of MMP-2 and/or MMP-9.

The instance of MMP suppressor factor comprises AG-3340, RO32-3555, RS13-0830, and following compounds: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxyl carbamyl-cyclopentyl)-amino]-propionic acid; 3-extroversion-3-[4-(4-fluoro-phenoxy)-phenylsulfonamido]-8-oxa--dicyclo is [3.2.1] octane-3-carboxyl acid oxyamide also; (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyl oxygen base)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-carboxylic acid hydroxamides; 4-[4-(4-fluoro-phenoxy)-phenylsulfonamido]-tetrahydrochysene-pyrans-4-carboxylic acid hydroxamides; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxyl carbamyl-cyclobutyl)-amino]-propionic acid; 4-[4-(4-chloro-phenoxy)-phenylsulfonamido]-tetrahydrochysene-pyrans-4-carboxylic acid hydroxamides; 3-[4-(4-chloro-phenoxy)-phenylsulfonamido]-tetrahydrochysene-pyrans-3-carboxylic acid hydroxamides; (2R, 3R) 1-[4-(4-fluoro-2-methyl-benzyl oxygen base)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-carboxylic acid hydroxamides; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxyl carbamyl-1-methyl-ethyl)-amino]-propionic acid; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxyl carbamyl-tetrahydrochysene-pyrans-4-yl)-amino]-propionic acid; 3-extroversion-3-[4-(4-chloro-phenoxy)-phenylsulfonamido]-8-oxa--dicyclo is [3.2.1] octane-3-carboxyl acid oxyamide also; In the 3-to-3-[4-(4-fluoro-phenoxy)-phenylsulfonamido]-8-oxa--dicyclo [3.2.1] octane-3-carboxyl acid oxyamide also; 3-[4-(4-fluoro-phenoxy)-phenylsulfonamido]-tetrahydrochysene-furans-3-carboxylic acid hydroxamides; With and pharmacy acceptable salt, solvate and hydrate.

The instance of signal transduction inhibitor comprises the medicament that can suppress EGFR (EGF-R ELISA) reaction, and for example EGFR antibody, EGF antibody reach and is the molecule of EGFR suppressor factor; VEGF (VEGF) suppressor factor; And the erbB2 acceptor inhibitor, for example be bonded to the organic molecule or the antibody of erbB2 acceptor, for example HERCEPTIN ^TM(Genentech company, South San Francisco, California, USA).

The EGFR suppressor factor is described in for example WO95/19970 (July 27 nineteen ninety-five is open), and WO98/14451 (on April 9th, 1998 is open) is in WO98/02434 (on January 22nd, 1998 is open) and the USP 5,747,498 (on May 5th, 1998 was given).The EGFR-suppressor factor comprise but be not limited to monoclonal antibody C225 and anti-EGFR 22Mab (the ImClone Systems company of New York, New York, USA), compound ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex company; Annandale; New Jersey, USA) and OLX-103 (Merck company, Whitehouse Station; New Jersey; USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen company, Hopkinton, Massachusetts).

The VEGF suppressor factor, for example (California USA), also can merge or co-administered with said composition for Sugen company, South San Francisco for SU-5416 and SU-6668.The VEGF suppressor factor is described in for example WO99/24440 (on May 20th, 1999 is open), PCT International Application PCT/IB99/00797 (on May 3rd, 1999 filed an application), WO95/21613 (August 17 nineteen ninety-five is open), WO99/61422 (on December 2nd, 1999 is open); USP 5,834,504 (on November 10th, 1998 was given), WO98/50356 (on November 12nd, 1998 is open); USP 5,883,113 (on March 16th, 1999 was given), USP 5; 886,020 (on March 23rd, 1999 was given), USP 5; 792,783 (on August 11st, 1998 was given), WO99/10349 (on March 4th, 1999 is open); WO97/32856 (on September 12nd, 1997 is open), WO97/22596 (on June 26th, 1997 is open), WO98/54093 (on December 3rd, 1998 is open); WO98/02438 (on January 22nd, 1998 is open), among WO99/16755 (on April 8th, 1999 is open) and the WO98/02437 (on January 22nd, 1998 is open), it is for reference that it all incorporates this paper into it in full.Other instance of some specificity VEGF suppressor factor be IM862 (Cytran company, Kirkland, Washington, USA); Anti-VEGF monoclonal antibody rhuMAb-VEGF (Genentech company, South San Francisco, California); And blood vessel enzyme (angiozyme), a kind of synthetic kernel carbohydrase, derive from Ribozyme (Boulder, Colorado) with Chiron (Emeryville, California).

The ErbB2 acceptor inhibitor, (Texas USA) can and use the said composition administration with 2B-1 (Chiron) to for example GW-282974 (Glaxo Wellcome plc), and monoclonal antibody AR-209 for Aronex pharmaceuticals, Woodlands.This eka-osmium rbB2 suppressor factor comprises at WO98/02434 (on January 22nd, 1998 is open), WO99/35146 (on July 15th, 1999 is open), WO99/35132 (on July 15th, 1999 is open); WO98/02437 (on January 22nd, 1998 is open), WO97/13760 (on April 17th, 1997 is open), WO95/19970 (July 27 nineteen ninety-five is open); USP 5; 587,458 (on December 24th, 1996 was given) and USPs 5,877; Described in 305 (on March 2nd, 1999 was given) those, it is for reference that its each piece of writing is all incorporated this paper into it in full.Can be used for ErbB2 acceptor inhibitor of the present invention and also be described in the U.S. Provisional Application of submitting on January 27th, 1,999 60/117; In 341; And in the U.S. Provisional Application of submitting on January 27th, 1,999 60/117,346, it is for reference that this two application is all incorporated this paper into it in full.

Spendable other anti-proliferative agent comprises the suppressor factor of enzyme process farnesyl protein matter transferring enzyme; With the suppressor factor of receptor tyrosine kinase PDGFr, be included in the compound that discloses and ask for protection in the following U.S. Patent application: 09/221946 (on December 28th, 1998 filed an application); 09/454058 (on December 2nd, 1999 filed an application); 09/501163 (on February 9th, 2000 filed an application); 09/539930 (on March 31st, 2000 filed an application); 09/202796 (on May 22nd, 1997 filed an application); 09/384339 (on August 26th, 1999 filed an application); And 09/383755 (on August 26th, 1999 filed an application); And in following U.S. Provisional Patent Application, disclose and the compound of asking for protection: 60/168207 (on November 30th, 1999 filed an application); 60/170119 (on December 10th, 1999 filed an application); 60/177718 (on January 21st, 2000 filed an application); 60/168217 (on November 30th, 1999 filed an application) and 60/200834 (on May 1st, 2000 filed an application).It is for reference that each aforementioned patent applications and temporary patent application are all incorporated this paper into it in full.

Compsn of the present invention also can use with other medicament that can be used for treating abnormal cell growth or cancer; Include but not limited to strengthen the medicament of anti tumor immune response; CTLA4 (cytotoxic lymphocyte antigen 4) antibody for example, and other can block the medicament of CTLA4; And anti-proliferative agent, for example other farnesyl-protein matter transferase inhibitor.Can be used for specific CTL A4 antibody of the present invention, be included in described in the U.S. Provisional Application 60/113,647 (on December 23rd, 1998 filed an application) those, it is for reference that it incorporates this paper in full into.

Definition

Only if description is arranged in addition, otherwise the following term that in this specification sheets and claim, uses has the implication that hereinafter is discussed.The variable that in this part, defines, for example R, x, n etc. only supply this paragraph internal reference, are not to mean to have as being used in the outer same meaning of this definitional part.Have, many groups of definition can be chosen wantonly and be substituted here again.Typical substituent inventory is an illustrative in this definitional part, is not intended to limit the defined substituting group in other places in patent specification and the claim.

" alkyl " is meant the radical of saturated aliphatic hydrocarbyl group, comprises 1 to 20 carbon atom, is preferably 1 to 12 carbon atom, is more preferably 1 to 8 carbon atom, or 1 to 6 carbon atom, or the straight chain and the branched group of 1 to 4 carbon atom." low alkyl group " refers in particular to the alkyl with 1 to 4 carbon atom.The instance of alkyl comprise methyl, ethyl, propyl group, 2-propyl group, just-butyl, isobutyl-, tert-butyl, amyl group etc.Alkyl can be substituted or not be substituted.Typical case's substituting group comprise naphthenic base, aryl, heteroaryl, assorted alicyclic, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, artyl sulfo, cyanic acid, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxyl, O-carboxyl, nitro, siloyl group, amino and-NR ^xR ^y, R wherein ^xWith R ^ySystem independently is selected from five of hydrogen, alkyl, naphthenic base, aryl, carbonyl, ethanoyl, alkylsulfonyl, trifluoromethane sulfonyl group and merging-or six-unit alicyclic ring of mixing.

" naphthenic base " is meant 3 to 8 yuan of full carbon monocycles; Full carbon 5-unit/6-unit or 6-unit/6-unit condensed dicyclo; Or the polycyclic fused rings (" condensing " loop systems meaning be meant in this system each encircle each other ring in the system therewith have an adjacent carbons to) group; Wherein one or more rings can contain one or more pairs of keys, but none has complete conjugated pi-electronic system in the said ring.The instance of naphthenic base is (but being not limited to) Trimetylene, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, cyclohexadiene, diamantane, suberane, cycloheptatriene etc.Naphthenic base can be and is substituted or is not substituted.Typical case's substituting group comprise alkyl, aryl, heteroaryl, assorted alicyclic, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, artyl sulfo, cyanic acid, halogen, carbonyl, thiocarbonyl, C-carboxyl, O-carboxyl, O-carbamyl, N-carbamyl, C-amido, N-amido, nitro, amino and-NR ^xR ^y, R wherein ^xWith R ^ySystem defines like preceding text.The illustrative example of naphthenic base is following derived from (but being not limited to):

" thiazolinyl " is meant the alkyl of being made up of at least two carbon atoms and at least one carbon-to-carbon double bond as defining among this paper.Representative example includes but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-crotonyl etc.

" alkynyl " is meant the alkyl of being made up of at least two carbon atoms and at least one carbon-to-carbon triple bond as defining among this paper.Representative example includes but not limited to ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.

" aryl " is meant the full carbon monocycle shape or the many cyclic groups of fused rings of 6 to 12 carbon atoms, has complete conjugated pi-electronic system.The instance of aryl is but is not limited to phenyl, naphthyl and anthryl.Aryl can be substituted or not be substituted.Typical case's substituting group comprises halogen, trihalogenmethyl, alkyl, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, artyl sulfo, cyanic acid, nitro, carbonyl, thiocarbonyl, C-carboxyl, O-carboxyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, alkylsulfonyl, amino reaching-NR ^xR ^y, R wherein ^xWith R ^yDefine like preceding text.

" heteroaryl " is meant the monocycle shape or the fused rings of 5 to 12 annular atomses, contains one, two, three or four ring hetero atom that is selected from N, O and S, and all the other annular atomses are C, and in addition, has complete conjugated pi-electronic system.The instance that is not substituted heteroaryl is but is not limited to pyrroles, furans, thiophene, imidazoles,

azoles, thiazole, pyrazoles, pyridine, pyrimidine, quinoline, isoquinoline 99.9, purine, tetrazolium, triazine and carbazole.Heteroaryl can be substituted or not be substituted.Typical case's substituting group comprises alkyl, naphthenic base, halogen, trihalogenmethyl, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, artyl sulfo, cyanic acid, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxyl, O-carboxyl, sulfinyl, alkylsulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino reaching-NR ^xR ^y, R wherein ^xWith R ^yDefine like preceding text.

Pharmaceutically acceptable heteroaryl is formulated into pharmaceutical composition for enough stable to be connected to compound of the present invention, and the heteroaryl that is given the patient who needs subsequently.

The instance of typical case's monocycle shape heteroaryl includes but not limited to:

Suitably the instance of fused ring heteroaryl includes but not limited to:

" assorted alicyclic " or " heterocycle " are meant monocycle or fused rings, in ring, have 3 to 12 annular atomses, and one of them or two annular atomses are for being selected from N, O and S (O) _nThe heteroatoms of (wherein n is 0,1 or 2), all the other annular atomses are C.Said ring also can have one or more pairs of keys.But said ring does not have complete conjugated pi-electronic system.In addition, one or more annular atomses can be replaced by oxo group.The saturated assorted alicyclic examples of groups that is fit to includes but not limited to:

Being fit to the unsaturated assorted alicyclic examples of groups of part includes but not limited to:

Heterocyclic group is optional to be replaced by one or two substituting group, and substituting group independently is selected from halogen, low alkyl group, by the low alkyl group of carboxyl substituted, ester hydroxyl or list or dialkyl amido.

" hydroxyl " is meant-the OH group.

" alkoxyl group " be meant-O-(alkyl) or-O-(not being substituted naphthenic base) both.Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.

" halogenated alkoxy " is meant-O-(haloalkyl).Representative example includes but not limited to trifluoromethoxy, tribromo methoxyl group etc.

" aryloxy " be meant as this paper definition-the O-aryl or-the O-heteroaryl.Representative example includes but not limited to phenoxy, pyridyl oxygen base, furyl oxygen base, thienyl oxygen base, pyrimidyl oxygen base, pyrazinyl oxygen base etc., and verivate.

" sulfydryl " is meant-the SH group.

" alkylthio " be meant-S-(alkyl) or-S-(not being substituted naphthenic base).Representative example includes but not limited to methylthio group, ethylmercapto group, rosickyite base, butylthio, ring rosickyite base, ring butylthio, ring penta sulfenyl, hexamethylene sulfenyl etc.

" artyl sulfo " be meant as this paper definition-the S-aryl or-the S-heteroaryl.Representative example includes but not limited to thiophenyl, pyridyl sulfenyl, furyl sulfenyl, thienyl sulfenyl, pyrimidine-based sulfur-base etc., and verivate.

" acyl group " or " carbonyl " be meant-C (O) R " group, wherein R " be selected from hydrogen, low alkyl group, trihalomethyl group, unsubstituted naphthenic base, optional by one or more (being preferably one, two or three) substituted aryl of substituting group (substituting group be selected from low alkyl group, trihalomethyl group, low-carbon alkoxy, halogen and-NR ^xR ^yGroup), optional by one or more (being preferably one, two or three) substituted heteroaryl of substituting group (combining) through ring carbon (substituting group be selected from low alkyl group, tri haloalkyl, low-carbon alkoxy, halogen and-NR ^xR ^yGroup) and optional by one or more (being preferably one, two or three) substituting group substituted assorted alicyclic (combining) through ring carbon (substituting group be selected from low alkyl group, tri haloalkyl, low-carbon alkoxy, halogen and-NR ^xR ^yGroup).Representative acyl group includes but not limited to ethanoyl, trifluoroacetyl group, benzoyl-etc.

" aldehyde " is meant wherein R " is the acyl group of hydrogen.

" sulfo-acyl group " or " thiocarbonyl " be meant-" group, wherein R " define like preceding text C (S) R.

" thiocarbonyl " be meant-" group, wherein R " define like preceding text C (S) R.

" C-carboxyl " is meant-C that " group, wherein R " define like preceding text (O) OR.

" O-carboxyl " is meant-OC that " group, wherein R " define like preceding text (O) R.

" ester " be meant-C (O) OR " group, wherein R " is like this paper definition, but R " can not be hydrogen.

" ethanoyl " is meant-C (O) CH ₃Group.

" halogen " is meant fluorine, chlorine, bromine or iodine, is preferably fluorine or chlorine.

" trihalomethyl group " is meant the methyl with three halogenic substituents, for example trifluoromethyl.

" cyanic acid " is meant-C ≡ N group.

" sulfinyl " is meant-S (O) R, and " group, wherein except defining like preceding text, R " also can be hydroxyl.

" alkylsulfonyl " is meant-S (O) ₂" group, wherein except defining like preceding text, R " also can be hydroxyl to R.

" S-sulfonamido " is meant-S (O) ₂NR ^xR ^yGroup, wherein R ^xWith R ^yDefine like preceding text.

" N-sulfonamido " is meant-NR ^xS (O) ₂R ^yGroup, wherein R ^xWith R ^yDefine like preceding text.

" O-carbamyl " is meant-OC (O) NR ^xR ^yGroup, wherein R ^xWith R ^yDefine like preceding text.

" N-carbamyl " is meant R ^yOC (O) NR ^x-group, wherein R ^xWith R ^yDefine like preceding text.

" O-thiocarbamyl " is meant-OC (S) NR ^xR ^yGroup, wherein R ^xWith R ^yDefine like preceding text.

" N-thiocarbamyl " is meant R ^yOC (S) NR ^x-group, wherein R ^yWith R ^xDefine like preceding text.

" amino " is meant-NR ^xR ^yGroup, wherein R ^xWith R ^yBe hydrogen.

" C-amido " is meant-C (O) NR ^xR ^yGroup, wherein R ^xWith R ^yDefine like preceding text.

" N-amido " is meant R ^xC (O) NR ^y-group, wherein R ^xWith R ^yDefine like preceding text.

" nitro " is meant-NO ₂Group.

" haloalkyl " meaning is meant and is preferably low alkyl group by alkyl, and it is replaced by one or more identical or different halogen atoms, for example-and CH ₂Cl ,-CF ₃,-CH ₂CF ₃,-CH ₂CCl ₃Deng.

" hydroxyalkyl " meaning is meant and is preferably low alkyl group by alkyl that it is replaced by one, two or three hydroxyl; Methylol, 1 or 2-hydroxyethyl, 1 for example, 2-, 1,3-or 2,3-dihydroxypropyl etc.

" aralkyl " meaning is meant and is preferably low alkyl group by alkyl that it is replaced by the aryl like the preceding text definition; For example-CH ₂Phenyl ,-(CH ₂) ₂Phenyl ,-(CH ₂) ₃Phenyl, CH ₃CH (CH ₃) CH ₂Phenyl etc., and verivate.

" heteroaralkyl " meaning is meant and is preferably low alkyl group by alkyl that it is replaced by heteroaryl; For example-CH ₂Pyridyl ,-(CH ₂) ₂Pyrimidyl ,-(CH ₂) ₃Imidazolyl etc., and verivate.

" alkyl monosubstituted amino " meaning is meant group-NHR, and wherein R is alkyl or unsubstituted naphthenic base; For example methylamino-, (1-methylethyl) amino, hexamethylene amino etc.

" dialkyl amido " meaning is meant group-NRR, and wherein each R independently is alkyl or unsubstituted naphthenic base; Dimethylamino, diethylin, (1-methylethyl)-ethylamino, cyclohexyl methylamino-, cyclopentyl methylamino-etc.

" optional " or " choose " look like be meant described subsequently incident or situation can but may not take place, and this description comprises the situation that this incident or situation wherein take place, and the situation that this incident or situation wherein do not take place.For example, " optional by the substituted heterocyclic radical of alkyl " meaning be meant this alkyl can but may not exist, and this description comprises wherein heterocyclic radical by the substituted situation of alkyl, and wherein heterocyclic radical not by the substituted situation of alkyl.

" pharmaceutical composition " is meant the compound described in one or more this paper; Or on its physiology/pharmacy acceptable salt, solvate, hydrate or prodrug, with other chemical ingredients for example on the physiology/mixture of pharmaceutically acceptable carrier and vehicle.The purpose of pharmaceutical composition is to help the administration of compound to biology.

Use in this article " on the physiology/and pharmaceutically acceptable carrier " be not meant and can cause significant stimulation biology, and can not eliminate the BA of the compound that gives and the carrier or the thinner of character.

" pharmaceutically acceptable vehicle " is meant the nonreactant that is added in the pharmaceutical composition with further promotion compound administration.The instance of vehicle includes but not limited to lime carbonate, calcium phosphate, various carbohydrate and dissimilar starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.

The term " pharmacy acceptable salt " that uses in this article is meant the biological effectiveness of maintenance parent compound and the salt of character.This type salt comprises:

(1) acid salt; It can be via the free alkali and the inorganic acids of parent compound; For example hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, sulfuric acid and perchloric acid etc.; Or and organic acid, for example acetate, oxalic acid, (D) or (L) reaction such as oxysuccinic acid, maleic acid, methanesulfonic, ethane sulfonic acid, right-toluenesulphonic acids, salicylic acid, tartrate, Hydrocerol A, succsinic acid or propanedioic acid and obtaining; Or

(2) when the acid proton that exists in the parent compound by metals ion for example when alkalimetal ion, alkaline earth metal ion or aluminum ion displacement; Or with organic bases formed salt during coordination such as thanomin, diethylolamine, trolamine, Apiroserum Tham, N-methyl glucoside amine for example.

" PK " is meant receptor protein tyrosine kinase (RTK), non-acceptor or " cell " Tyrosylprotein kinase (CTK) and serine-threonine kinase (STK).

" regulating effect " or " adjusting " is meant the change of RTK, CTK and STK catalytic activity.Particularly; Adjusting is meant the activation of RTK, CTK and STK catalytic activity; Be preferably the activation or the inhibition of RTK, CTK and STK catalytic activity, according to the concentration of compound that RTK, CTK or STK exposed or salt and decide, or more preferably be RTK, the inhibition of CTK and STK catalytic activity.

" catalytic activity " is meant the speed of the phosphorylation of tyrosine under the direct or indirect influence of RTK and/or CTK, or the speed of Serine and the phosphorylation of Threonine under the direct or indirect influence of STK.

" contact " is to instigate The compounds of this invention and target P K together; Its mode causes compound can influence the catalytic activity of PK, no matter is directly, and meaning is promptly through interacting with kinases itself; Or indirectly, meaning i.e. another kind of interaction of molecules through being relied on kinase whose catalytic activity.Should " contact " can anticipate and promptly in test tube, petri diss or analogue, realize in " in vitro ".In test tube, contact can only relate to compound and purpose PK, or it can relate to full cell.Cell also can be held or grow in the Tissue Culture Dish, and contacts in this environment with compound.In this connection, specific compound influences the ability of PK associated disorders, and meaning is the compound I C of hereinafter definition ₅₀, can be in vivo measuring before compound uses, wherein more complicated lived biology is used in attempt.For the outer cell of biology, there is several different methods to exist, and known by those skilled in the art, so that PK contacts with compound, include but not limited to direct cell microinjection and the multiple membrane carrier technology of striding.

" in vitro " be meant the program of in artificial environment, carrying out, such as but not limited in test tube or substratum.

" in vivo " be meant the program of in lived biology, carrying out, such as but not limited to mouse, rat or rabbit.

" PK associated disorders ", " PK drive obstacle " reach " unusual PK is active " and all refer to a kind of patient's condition, it is characterized by inappropriately, and meaning i.e. deficiency, or more common be over-drastic PK catalytic activity, wherein specific PK can be RTK, CTK or STK.Inappropriate catalytic activity can be caused by following arbitrary aspect: (1) PK in the cell of not expressing PK usually expresses; (2) PK that increases expresses; Cause hyperplasia, differentiation and/or the growth do not expected; Or the PK that (3) reduce expresses, cause hyperplasia, differentiation and/or growth do not expect reduce.The overactivity of PK is meant the amplification of the gene of the specific PK of coding; Or the to a certain degree active generation of PK; It can be interrelated with hyperplasia, differentiation and/or retardation of growth (meaning promptly, when the level of PK increased, the seriousness of one or more symptoms of cell obstacle increased).Active deficiency is a reverse situation certainly, and wherein when the active level of PK reduced, the seriousness of one or more symptoms of cell obstacle can increase.

" treatment (treat) ", " treatment (treating) " reach " (treatment treatment) " and are meant and alleviate or eliminate the cell obstacle that PK mediates and/or the method for its subsidiary symptom.Particularly about cancer, these terms only are meant that the expection life time of the individuality of suffering from cancer will be increased, or one or more symptoms of said disease will be reduced.

" biology " is meant any lived entity that comprises at least a cell.Lived biology can be simply as single eukaryotic cell, or complicated like Mammals, comprises the mankind.

" significant quantity in the treatment " is meant the amount of the compound that gives, and this amount will make by one or more symptom rings of treatment obstacle and separate to a certain degree.About treatment for cancer, significant quantity is meant and has following at least a on amount in the treatment:

(1) reduces the tumour size;

(2) suppress (meaning promptly slows to a certain degree, is preferably to stop) metastases;

(3) suppress tumor growth to (meaning promptly slows to a certain degree, is preferably to stop) to a certain degree and

(4) make one or more symptoms that join with related to cancer, ring is separated to (or being preferably elimination) to a certain degree.

" monitoring " meaning is meant observes or detects the effect that makes compound and express the cells contacting of specific PK.The effect of observing or detecting can be the change of cell phenotype, PK catalytic activity or combines the interactional change of counterpart at PK with natural.The technology of observing or detect this type effect is well known in the art.This effect be selected from the change of cell phenotype do not have the change of change, said protein kinase catalytic activity or do not have change or aspect the present invention is last in, said protein kinase combines the interactional change of counterpart or does not have change with natural.

" cell phenotype " is meant the external manifestation of the biological function of cell or tissue or cell or tissue.The instance of cell phenotype is but is not limited to cell size, cell growth, hyperplasia, cytodifferentiation, cell survival, apoptosis and nutrition absorption and utilizes.This type phenotypic characteristic can pass through commercial measurement well known in the art.

" natural combination counterpart " is meant the polypeptide that in cell, is bonded to specific PK.Natural combination counterpart can play a role in the transmitting signal in PK Mediated Signal Transduction process.But natural combination counterpart self shows as through increasing or reduce the natural counterpart mixture that combines of PK/ of concentration with the interactional change of PK, and the result is the change observed of PK mediation signal transduction ability.

Term " optically pure ", " enantiomeric pure ", " the pure enantiomer of using in this article " reaches " optical purity enantiomer " meaning and is meant a kind of enantiomer of inclusion compound, and do not contain the compsn of the opposite enantiomer of this compound in fact.Typical case's optical pure compound comprises a kind of enantiomer greater than about 80 these compounds of weight %; With the opposite enantiomer that is lower than about 20 these compounds of weight %; A kind of enantiomer more preferably greater than about 90 these compounds of weight %; With the opposite enantiomer that is lower than about 10 these compounds of weight %, even more preferably greater than a kind of enantiomer of about 95 these compounds of weight %, with the opposite enantiomer that is lower than about 5 these compounds of weight %; And most preferably greater than a kind of enantiomer of about 97 these compounds of weight %, with the opposite enantiomer that is lower than about 3 these compounds of weight %.

Specify

About the general approach of synthetic The compounds of this invention, can find in the embodiment part in this article.

Unless otherwise; Otherwise this paper is for all denotions of The compounds of this invention; Comprise and censure its salt, solvate, hydrate and mixture, and censure solvate, hydrate and the mixture of its salt, comprise that its polymorphic form, steric isomer reach with isotope-labeled form.

Pharmacy acceptable salt comprises acid salt and alkali salt (comprising two salt).The acid salt that is fit to is formed by the acid that forms non-toxic salts.Instance comprises acetate; Aspartate; Benzoate; Benzene sulfonate; Bicarbonate/carbonate; Hydrosulfate/vitriol; Borate; Camsilate; Citrate trianion; Ethane disulfonate; Ethane sulfonate; Formate; Fumarate; Gluceptate; Gluconate; Glucuronate; Hexafluorophosphate; Hibenzic acid salt; Hydrochloride/muriate; Hydrobromate/bromide; Hydriodate/iodide; Isethionate; Lactic acid salt; Malate; Maleic acid salt; Malonate; Methane sulfonates; Methylsulfate; Naphthoate; The 2-naphthalenesulfonate; Nicotinate; Nitrate salt; Orotate; Oxalate; Palmitate; Embonate; Phosphate/phosphor acid hydrogen salt/dihydrogen phosphate; Saccharate; Stearate; SUMATRIPTAN SUCCINATE; Tartrate; Tosylate and trifluoroacetate.

The alkali salt that is fit to is formed by the alkali that forms non-toxic salts.Embodiment comprises aluminium, l-arginine, dibenzyl-ethylenediamin, calcium, choline, diethylamine, glycol amine, glycocoll, Methionin, magnesium, meglumine, thanomin, potassium, sodium, Apiroserum Tham and zinc salt.

About the summary of suitable salt, " drug salts handbook: character, selection and purposes " (Wiley-VCH, Weinheim, Germany, 2002) that can consult Stahl and Wermuth, it is for reference that its disclosure is incorporated this paper in full with it.

When needing, the pharmaceutically-acceptable salts of The compounds of this invention can be easily through with compound with the solution of the acid of wanting or alkali mix.This salt can be from solution precipitation, and collects through filtering, and maybe can reclaim through the evaporation of solvent.Degree of ionization in the salt can change to almost unionization from complete ionize.

The compounds of this invention is solvent chemical combination and two kinds of forms existence of solvent chemical combination not.Term " solvate " is used in this article, comprises the molecular complex of The compounds of this invention and one or more pharmaceutically acceptable solvent molecules (for example ethanol) with description.When solvent is water, adopt term " hydrate ".According to pharmaceutically acceptable solvate of the present invention, comprise hydrate and wherein the crystalline solvent can the substituted solvate of isotropic substance, for example D ₂O, d ₆-acetone, d ₆-DMSO.

Also involved person within the scope of the invention is a mixture, Runge-Kutta integration for example, medicine-host's inclusion complex wherein, the solvate contrast mentioned with preamble, medicine and host with stoichiometric quantity or non-chemically calculated amount exist.Also comprise the medicinal composition that contains two kinds or more kinds of organic and/or inorganic components, this composition can be stoichiometric quantity or calculated amount non-chemically.Formed mixture can be ionize, partial ionization or without ionize.About the summary of this type mixture, can consult the J Pharm Sci of Haleblian, 64(8), 1269-1288 (in August, 1975), it is for reference that its disclosure is incorporated this paper in full with it.

Also within the scope of the invention be the polymorphic form of The compounds of this invention, prodrug and isomer (comprising optics, geometry and tautomerism isomer).

The verivate of The compounds of this invention itself can have few or not have pharmacological activity, but when being given sufferer, can be converted to The compounds of this invention, for example through hydrolytic scission.This analog derivative is called as " prodrug ".Further information about the prodrug purposes; Can consult " as the prodrug (Pro-drugs as Novel Delivery Systems) of novel transmission system "; The 14th volume, ACS symposial series (T Higuchi and W Stella) is with " the biological reversible carrier in medicinal design (Bioreversible Carriers in Drug Design) "; Pergamon press; 1987 (E B Roche writes, united states drug association), it is for reference that its disclosure is all incorporated this paper into it in full.

Can for example process according to prodrug of the present invention through the suitable functionality that is present in the The compounds of this invention with some part displacement; This part is called " fore portion " by those skilled in the art; Like " prodrug design (Ddesign of Prodrugs) " (Elsevier that is showing by Hbundgaard; 1985), it is for reference that its disclosure is incorporated this paper in full with it.

Some instances of prodrug comprise according to the present invention:

(i) contain carboxylic functionality at compound and (in situation COOH), be its ester, for example with (C ₁-C ₈) alkyl displacement hydrogen;

(ii) contain the carbinol-functional degree and (in situation OH), be its ether, for example with (C at compound ₁-C ₆) alkanoyloxymethyl displacement hydrogen; And

(iii) contain uncle or secondary amino group functionality (NH at compound ₂Or-NHR, wherein in the situation of R ≠ H), be its acid amides, for example with (C ₁-C ₁₀) one or two hydrogen of alkyloyl displacement.

According to other embodiment of the displacement group of preamble instance and the instance of other prodrug type, can in the mentioned reference of preamble, find.

At last, some The compounds of this invention itself can be useed the prodrug of other The compounds of this invention as.

The The compounds of this invention that contains one or more unsymmetrical carbons can two kinds or the existence of more kinds of steric isomer.Contain in the situation of thiazolinyl or alkenylene at The compounds of this invention, how much suitable/anti-(or Z/E) isomer are possible.Contain in the situation of ketone for example or oximido or aromatics part at compound, tautomeric isomery (" tautomerism ") can take place.The simplification compound can show the isomery above a type.

Involved within the scope of the invention be all steric isomers, geometrical isomer and the tautomeric form of The compounds of this invention, comprise the compound of the isomery that show to surpass a type, and its one or more mixture.Also comprise for acid salt or alkali salt, wherein counter ion are optically active, for example D-lactate or L-Methionin, or be racemic, for example DL-tartrate or DL-l-arginine.

Suitable/trans isomer can separate through the routine techniques that those skilled in the art knew, for example chromatography and fractional crystallization.

About the routine techniques of the indivedual enantiomers of preparation/separation, comprise from the chirality of the optical purity precursor that is fit to and synthesizing, or the parsing of racemoid (or racemoid of salt or verivate), use for example chirality HPLC (HPLC).

Perhaps, racemoid (or racemize precursor) can react with the optically active compound that is fit to is for example pure, or contains in the situation of acidity or basic moiety at compound, with acid or for example tartrate or the reaction of 1-phenyl-ethyl amine of alkali.Formed diastereo-isomerism mixture can separate through chromatography and/or fractional crystallization, and diastereomer a kind of or both, through the mode that those skilled in the art knew, is converted to its corresponding pure enantiomer.

Chipal compounds of the present invention (and chiral precurser) can use chromatography, is HPLC on the typical case, on asymmetric resin; Use comprises the moving phase of hydrocarbon, is heptane or hexane on the typical case, contains 0 to 50% Virahol; The typical case is last to be 2 to 20%; With 0 to 5% alkylamine, the typical case is last to be 0.1% diethylamine, with the form acquisition of enantiomer enrichment.The mixture of the concentrated acquisition enrichment of elutant.

Steric isomer is heaped body and can be separated through routine techniques known to those skilled in the art; Consult, for example by ELEliel outstanding " stereochemistry of organic cpds (Stereochemistry of Organic Compounds) " (Wiley, NewYork, 1994).It is for reference that its disclosure is incorporated this paper in full with it.

The present invention also comprises isotope-labeled The compounds of this invention, and wherein one or more atoms are had the same atoms ordinal number, but atomic mass or total mass number are different from usually in the atomic mass of occurring in nature discovery or the atomic substitutions of total mass number.Be fit to be included in the isotropic substance that isotopic instance in the The compounds of this invention comprises hydrogen, for example ²H with ³H; The isotropic substance of carbon, for example ¹¹C, ¹³C reaches ¹⁴C; The isotropic substance of chlorine, for example ³⁶Cl; The isotropic substance of fluorine, for example ¹⁸F; The isotropic substance of iodine, for example ¹²³I with ¹²⁵I; The isotropic substance of nitrogen, for example ¹³N with ¹⁵N; The isotropic substance of oxygen, for example ¹⁵O, ¹⁷O reaches ¹⁸O; The isotropic substance of phosphorus, for example ³²P; And the isotropic substance of sulphur, for example ³⁵S.Some isotope-labeled The compounds of this invention, for example incorporate into radioisotopic those, can be used in medicine and/or the research of substrate tissue distribution.The ri tritium ( ³H) with carbon-14 ( ¹⁴C), in view of it is easy to mix and proofing unit easily, so be specially adapted to this project.With heavier isotropic substance for example deuterium ( ²H) replace, can provide because than some treatment advantage that greater metabolic stability property caused, the in vivo transformation period that for example increases or the dose requirements of reduction, and possibly be preferred in some cases therefore.With positron radiation property isotropic substance for example ¹¹C, ¹⁸F, ¹⁵O reaches ¹³N replaces, and can be used for positron emission scanning (PET) research, is used to check that the substrate acceptor captures.

Isotope-labeled The compounds of this invention; Generally can pass through routine techniques known to those skilled in the art; Or through those the method described in similar this paper, the reagent that uses the isotope-labeled reagent that is fit to substitute the un-marked that adopts is in other cases processed.

Pharmaceutically acceptable solvate according to the present invention comprise wherein the crystalline solvent can by isotropic substance substituted those, D for example ₂O, d ₆-acetone, d ₆-DMSO.

Desire supply the The compounds of this invention of pharmaceutical use can crystalline or amorphous product or its mixture give.They can be through the for example method of deposition, crystallization, freeze-drying, spraying drying or evaporation drying, with the form acquisition of for example solid plug, powder or film.Microwave or radio-frequency seasoning can supply the use of this project.

Compound can be separately or with one or more other The compounds of this invention, or with one or more other medicines (or with its any combination) administration.Generally speaking, will with the form administration of one or more pharmaceutically acceptable vehicle bonded preparations.Term " vehicle " is in this article in order to describe any composition beyond the The compounds of this invention.The selection of vehicle will be decided according to some factors to a great extent, and for example specific administration pattern, vehicle are to solubleness and the effect of stability and the character of formulation.

Be applicable to the pharmaceutical composition of sending The compounds of this invention, and the method for preparing them, will be very tangible to one skilled in the art.This based composition and method for making thereof for example can be consulted " RemingtonShi pharmaceutical science (Remington ' s Pharmaceutical Sciences) ", and the 19th edition (Mack publishing company, 1995), it is for reference that its disclosure is incorporated this paper in full with it.

Oral administration

Compound Orally-administrable of the present invention.Oral administration can comprise to be swallowed, so that let this compound get into gi tract; Maybe can use oral cavity or sublingual administration, to let this compound directly get into the blood flow from mouth.

The preparation that is appropriate to oral administration comprises solid preparation, such as tablet; The capsule that comprises particulate, liquid or powder; Lozenge (comprising liquid filling); Masticatory; Many-and nanoparticle; Gel; Sosoloid; Liposome; Film; Ovulum; Sprays and liquid preparation.

Liquid preparation comprises suspension-s, solution, syrup and elixir.This preparation also can use as stopping composition in soft or hard capsule, and its typical case comprises supporting agent (for example water, ethanol, polyoxyethylene glycol, Ucar 35, methylcellulose gum or suitable oil) and one or more emulsifying agents and/or suspension agent.Liquid preparation also can for example prepare from sachet through constituting solid again.

Compound of the present invention dissolving fast, quickly disintegrated formulation are used, and advocate (Expert Opinion in Therapeutic Patents) such as the expert who is described in the treatment patent, 11(6), those among the 981-986 (by beam (Liang) and old (Chen) (2001)).It is for reference that the disclosure of the document is incorporated this paper in full with it.

Concerning Tabules, this medicine can account for 1 weight % to 80 weight % of formulation according to dosage, and more the typical case accounts for 5 weight % to 60 weight % of formulation.Except this medicine, tablet generally includes disintegrating agent.The instance of disintegrating agent comprises sodium starch glycolate, sodium carboxymethyl-cellulose, ECG-505 salt, croscarmellose (croscarmellose) sodium, Crospovidone, Vinylpyrrolidone polymer, methylcellulose gum, Microcrystalline Cellulose, through the substituted hydroxypropylcellulose of short-chain alkyl, starch, pregelatinized starch and sodiun alginate.As a rule, this disintegrating agent will account for 1 weight % to 25 weight % of formulation, preferably account for 5 weight % to 20 weight %.

Usually the cohesion matter of using tackiness agent to give tablet formulation.Suitable binder comprises Microcrystalline Cellulose, gelatin, carbohydrate, polyoxyethylene glycol, natural and synthetic gum, Vinylpyrrolidone polymer, pregelatinized starch, hydroxypropylcellulose and Vltra tears.Tablet also can comprise thinner, such as lactose (monohydrate, spray-dired monohydrate, anhydrous and analogue), N.F,USP MANNITOL, Xylitol, Vadex, sucrose, Sorbitol Powder, Microcrystalline Cellulose, starch and dicalcium phosphate dihydrate.

Tablet also can be chosen wantonly and comprise tensio-active agent, such as sodium lauryl sulfate and Polysorbate 80; And glidant, such as silicon-dioxide and talcum.When existing, tensio-active agent can account for 0.2 weight % to 5 weight % of tablet; And glidant can account for 0.2 weight % to 1 weight % of tablet.

Tablet also comprises lubricant usually, such as the mixture of Magnesium Stearate, calcium stearate, Zinic stearas, FUMARIC ACID TECH GRADE stearate sodium and Magnesium Stearate and sodium lauryl sulfate.Lubricant accounts for 0.25 weight % to 10 weight % of tablet usually, preferably accounts for 0.5 weight % to 3 weight %.

Other possible composition comprises inhibitor, tinting material, seasonings, sanitas and taste screening agent.

Typical tablet comprises the highest about 80% medicine, about 10 weight % to the tackiness agent of about 90 weight %, about 0 weight % to the thinner of about 85 weight %, about 2 weight % to the disintegrating agent of about 10 weight % and the about 0.25 weight % lubricant to about 10 weight %.

Tablet mixture can directly or by cylinder compress, to form tablet.In addition, the mixture of tablet mixture or part can be before film-making through moistening, drying or fusion granulating, fusion is condensed or push.Last preparation can comprise one or more layers and can be coated or dressing not; Itself in addition also can be by encapsulated.

((horse a little you (Marcel) is worn gram (Dekker) work to tablet formulation to draw interest graceful (Lachman) by H. thunder Berman (Lieberman) and L. at " pharmaceutical dosage form: lozenge; the 1st (Pharmaceutical Dosage Forms:Tablets) "; New York; Discussion is arranged 1980), and it is for reference that its disclosure is incorporated this paper in full with it.

Solid preparation for oral administration can be prepared to become and promptly release and/or transfer and release.Transfer release formulation comprise delays-, continue-, pulse-, controlled-, target and sequencing release.

The accent release formulation that is fit to is described in USP the 6th, 106, in No. 864.The details of the release tech that other is fit to, for example high-energy dispersion-s and infiltration and coated particle can be people such as Verma, drug technique online (Pharmaceutical Technology On-line), 25 (2), 1-14 finds in (2001).Utilize chewing gum to reach controlled release, be described among the WO00/35298.The disclosure of these reference, it is for reference all to incorporate this paper in full into it.

Administered parenterally

Compound of the present invention also can be administered directly among blood flow, muscle or the internal.Suitable parenteral admin method comprises that intravenously, intra-arterial, intraperitoneal, sheath are interior, indoor, in the urethra, in the breastbone, encephalic, intramuscular and subcutaneous.The device that is appropriate to parenteral admin comprises pin (comprising micropin) syringe, needleless injector and infusion techn.

Parenteral formulation is typically the aqueous solution, and it can comprise vehicle, such as salt, glucide and buffer reagent (preferred pH is 3 to 9); But concerning some was used, they can more suitably be formulated as aseptic non-aqueous solution or the dried forms for being used in combination with suitable vehicle (such as aseptic, apirogen water).

Can use and easily obtain preparation this parenteral formulation (for example, through freeze-drying) under sterile state by the standard pharmaceutical technology that those skilled in the art knew.

Can use appropriate formulations technology (such as mixing the solubleness rising agent) to increase the solubleness of use The compounds of this invention in the preparation of parenteral solution.

The parenteral admin preparation can be formulated into promptly to be released and/or transfers and release.Transfer that release formulation comprises delays, continues, pulse, control, target and sequencing release.Compound of the present invention can be formulated into solid, semisolid or the thixotropic liquid that is used for through the storage storehouse administration (release that it can provide this active compound to change) of implanting.This type examples of formulations comprises stent and the PGLA microsphere through the medicine coating.

Topical

But compound of the present invention is topical to skin or mucous membrane also, that is, and and skin or through percutaneous drug delivery.The exemplary formulations that is used for this purpose comprises gel, hydrogel, lotion, solution, emulsifiable paste, ointment, spraying powder, dressing, foam, film, transdermal patches, wafer, implant, sponge, fiber, bandage and microemulsion.Also can use liposome.Typical supporting agent comprises alcohol, water, MO, whiteruss, white paraffin, glycerine, polyoxyethylene glycol and Ucar 35.Can mix penetration enhancer, for example can be referring to the J.Pharm Sci of Pfennig (Finnin) and the root that rubs (Morgan), 88(10), 955-958 (in October, 1999).The method of other topical comprises passes through through electroporation, ion-conductance that therapy, sound wave penetrate method (phonophoresis), ultrasound penetrates method (sonophoresis) and micropin or needleless (for example, Powderject ^TM, Bioject ^TMOr the like) injected delivery.It is for reference that the disclosure of these reference is all incorporated this paper into it in full.

Supply the preparation of topical to prepare to become promptly to release and/or transfer and release.Transfer release formulation comprise delays-, continue-, pulse-, controlled-, target and sequencing release.

Suction/intranasal administration

But compound of the present invention is also in the nose or pass through inhalation; Since typically being from the dry powder form of dry powder sucker (separately, as mixture, for example with the drying composite of lactose; Or be the blended component particles for example, mix with phosphatide (such as phosphatidylcholine)); Or be hang oneself pressurization container, pump, atomizer, spraying gun (being preferably the spraying gun that uses electrical fluid mechanics (electrohydrodynamics) to produce the fine mist thing) or sprinker (its can use or not use suitable propelling agent (such as 1,1,1; 2-Tetrafluoroethane or 1,1,1; 2; 3,3,3-HFC-227)) aerosol spray.In nose, using, this powder can comprise bioadhesive polymer, for example, and WOT Recovery Floc T or Schardinger dextrins.

This container, pump, atomizer, spraying gun or sprinker through pressurization comprises solution or the suspension-s that contains compound of the present invention; It comprises that ethanol for example, aqueous ethanolic solution or another kind of is appropriate to disperse, solubilising or prolong material that promoting agent discharges, as the propelling agent of solvent and optional tensio-active agent, such as three oleic acid sorbitan esters, oleic acid or lactic acid oligomer.

Before in being used in dry powder or suspension preparation, the pharmaceutical product micro mist is changed into the size (typical case is less than 5 microns) that is appropriate to suck transmission.This can realize through any suitable levigation method, such as spiral spray polishing, fluidised-bed spray polishing, treatment with supercritical fluid to form nanoparticle, high pressure homogenizing method or spray-drying process.

The capsule (for example, making from gelatin or Vltra tears), blister and the cartridge case that are used in sucker or the insufflator can be formulated into the powdered mixture that comprises compound of the present invention, suitable powder matrix (such as lactose or starch) and improvement in performance agent (such as l-leucine, N.F,USP MANNITOL or Magnesium Stearate).Lactose can be anhydrous or the monohydrate form, the preferred latter.Other suitable vehicle comprises VISOSE, glucose, SANMALT-S, Sorbitol Powder, Xylitol, fructose, sucrose and trehalose.

Can be used in and use the electrical fluid mechanics to produce the compound of the present invention that the each driving of suitable aqueous preparation in the spraying gun of fine mist thing can comprise 1 microgram to 20 milligram, and it drives volume and can be changed to 100 microlitres from 1 microlitre.Typical formulation can comprise compound of the present invention, Ucar 35, sterilized water, ethanol and sodium-chlor.Other can make the solvent that is used for replacing Ucar 35 comprise glycerine and polyoxyethylene glycol.

Can suitable seasonings (such as Therapeutic Mineral Ice and left-handed Therapeutic Mineral Ice) or sweeting agent (such as asccharin or soluble saccharin) be added to and this invention is intended to be used to suck/those preparations of intranasal administration.

Supply the preparation of suctions/intranasal administration to prepare to become promptly to release and/or transfer and release, use and for example gather (DL-lactic acid-common oxyacetic acid) (PGLA).Transfer release formulation comprise delays-, continue-, pulse-, controlled-, target and sequencing release.

In Diskus and aerocolloidal situation, dose unit utilizes valve to measure, and it sends the amount through metering.Typically arranged according to unit of the present invention, with give through the metering dosage or contain the The compounds of this invention " aerosol spraying " that will measure to some extent.Total per daily dose can single dose or is more generally given with the separate dose in all day.

Rectum/intravaginal administration

The compounds of this invention can give through rectum or vagina, for example is suppository, vaginal suppository or enema forms.Theobroma oil is traditional suppository base, but can use various surrogates when needing.

Supply the preparation of rectum/vagina administration to prepare to become promptly to release and/or transfer and release.Transfer release formulation comprise delays-, continue-, pulse-, controlled-, target and sequencing release.

Ophthalmic administration

Compound of the present invention also can be administered directly to eyes or ear, canonical form be splash into isoosmotic pressure, through the microparticle suspending liquid or the solution of pH adjustment, aseptic saline solution.Other preparation that is appropriate to eyes and ear administration comprises ointment, biodegradable (for example, absorbable gel sponge, collagen) and biological nondegradable (for example ZGK 5) implant, film (wafer), eyeglass and particulate or little bag system (such as big vesicle (niosomes) or liposome).((for example can mix polymkeric substance together such as crosslinked ROHM, Z 150PH, Hyaluronic Acid, cellulose polymer compound; Vltra tears, Natvosol or methylcellulose gum) or mixed polysaccharide polymkeric substance (for example, agarose gel)) and sanitas (such as benzalkonium chloride).This preparation also can be carried through iontophoresis.

Supply the preparation of eye/ear administration to prepare to become promptly to release and/or transfer and release.Transfer release formulation comprise delays-, continue-, pulse-, controlled-, target or sequencing release.

Other technology

Compound of the present invention can combine with soluble macromole entity (such as Schardinger dextrins and suitable verivate thereof or contain the polymkeric substance of polyoxyethylene glycol), and solubleness, dissolution rate, the taste that is used in any aforementioned mode of administration of mentioning with improvement covers, bioavailability and/or stability.

For example, found that the drug-cyclodextrin mixture is useful to most formulation and route of administration usually.Can use inclusion and non-inclusion complex the two.Except with the direct misfit of medicine, Schardinger dextrins can use as supplementary additive,, can be used as supporting agent, thinner or solubilizing agent that is.The most often be used in these purposes have α-, β-and γ-Huan Hujing, the example can find that in PCT publication number WO91/11172, WO 94/02518 and WO 98/55148 it is for reference that its disclosure is all incorporated this paper into it in full.

Dosage

The amount of the active compound that gives is according to being decided by the disposal of the seriousness of experimenter, obstacle or the patient's condition of being treated, medicine-feeding rate, compound and prescriber's judgement.But, effective dose typically every day every kg body weight about 0.001 to about 100 milligrams scope, be preferably about 0.01 to about 35 mg/kg/day, with single dose or the dosage that separates.As far as 70 kilograms of mankind, this is equivalent to about 0.07 to about 7000 mg/day, is preferably about 0.7 to about 2500 mg/day.In some cases; The dosage level that is lower than the aforementioned range lower limit possibly be more suitable for, and in other situation, also can use bigger dosage; And can not cause any harmful side effect, this bigger dosage typically to be distinguished into the administration that several less dosage supply all day.

The kit of accessory

Owing to possibly expect to give the combination of active compound; For example for treating the purpose of the specified disease or the patient's condition; So within the scope of the present invention, two kinds or more kinds of pharmaceutical composition (wherein at least a contain with good grounds compound of the present invention) can be combined in aptly and be fit to give jointly in the kit form of said composition.Therefore, kit of the present invention comprises two kinds or more kinds of separated drug compsn (the wherein at least a The compounds of this invention that contains), and the device that is used for keeping dividually said composition, for example the paper tinsel parcel of the bottle of container, separation or separation.The blister that be used for package troche, capsule etc. of the instance of this type kit for being familiar with.

Kit of the present invention is particularly suitable for giving different dosage forms, and for example oral and parenteral is used for giving separate compositions at interval with different dosages, or is used for adjusting each other separate compositions.For helping conformability, kit typically comprises the directions for use about administration, and can provide memory aid.

Embodiment

In following embodiment, " Et " meaning is meant ethyl, and " Ac " meaning is meant ethanoyl, and " Me " meaning is meant methyl, and " Ms " meaning is meant methane sulfonyl (CH ₃SO ₂), " iPr " meaning is meant sec.-propyl, " HATU " meaning is meant phosphofluoric acid 2-(7-azepine-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea

" Ph " meaning is meant phenyl, and " Boc " meaning is meant uncle-butoxy carbonyl, and " EtOAc " meaning is meant ETHYLE ACETATE, and " HOAc " meaning is meant acetate, " NEt ₃" or " Et ₃N " looking like is meant triethylamine, and " THF " meaning is meant THF, and " DIC " meaning is meant DIC; " HOBt " meaning is meant hydroxybenzotriazole, and " MeOH " meaning is meant methyl alcohol, and " i-PrOAc " looks like and is meant isopropyl acetate; " KOAc " meaning is meant potassium acetate; " DMSO " meaning is meant methyl-sulphoxide, and " AcCl " meaning is meant Acetyl Chloride 98Min., " CDCl ₃" looking like is meant the deuterate chloroform, " MTBE " meaning is meant methyl-tert-butyl ether, " DMF " meaning is meant N, " Ac ₂O " looking like is meant diacetyl oxide, " Me ₃SOI " looking like is meant iodate trimethylammonium sulfoxonium; and " DMAP " meaning is meant the 4-Dimethylamino pyridine; " dppf " meaning is meant the diphenylphosphine ferrocene, and " DME " meaning is meant ethylene glycol dimethyl ether (1, the 2-glycol dimethyl ether); the HOBT meaning is meant I-hydroxybenzotriazole, and EDC looks like and is meant 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide.

Provide following embodiment with explanation the present invention.But it should be understood that the present invention is not limited to specified conditions described in these embodiment or details.

Reagent can synthesize by shown in this paper, maybe can derive from commercial source (Aldrich for example, Milwaukee, WI; Acros, Morris Plains, NJ; Biosynth International, Naperville, IL; Frontier Seientific, Logan, UT; TCI America, Portland, OR; Combi-Blocks, San Diego, CA; Matrix Scientific, Columbia, SC; Acros, Morris Plains, NJ; Alfa Aesar, Ward Hill, MA; Apollo Scientific, UK; Deng) maybe can be synthetic through program as known in the art.

The synthetic u.s. patent application serial number of submitting on February 26th, 2,004 10/786 that is shown in of several particular agent; In 610; Its title is " as the aminoheteroaryl compounds of kinases inhibitor ", and among the corresponding International Application PCT/US2004/005495 of the same title of submitting on February 26th, 2004.Other reagent can synthesize through the program of revising wherein, and those skilled in the art can easily revise those programs to produce desired compound.Have, these reference comprise general procedure and the specific embodiment for preparing a large amount of heteroaryl amino compounds again, and those skilled in the art can easily revise this class method and embodiment, to prepare compound of the present invention.It is for reference that the disclosure of these reference is all incorporated this paper into it in full.

When quoting general or during the synthesis program of giving an example, those skilled in the art can easily determine the reagent that is fit to, if indication, then from the program extrapolation that should be general or gives an example.Provide some general procedures, as the embodiment of preparation specific compound.Those skilled in the art can easily revise this class method, with synthetic other compound.The R group meaning that it should be understood that in the general procedure to be shown is general and nonrestrictive, and not corresponding to the definition of R group in other places in this file.Each this R group is represented one or more chemical parts, and it can be also identical or different with the chemical part of identical R symbolic representation with other.Those skilled in the art can easily understand the scope of the R group that is fit in for example synthetic.Have again, be not substituted the expression of position in the structure that shows or censure in the general procedure, be for simplicity, and do not get rid of like the described replacement in this paper other places.For the special groups that possibly exist, no matter be as the R group in the general procedure or as the optional substituting group that does not show, be meant the description in this file rest part, comprise claim, general introduction and detailed description.

Some general procedures are with reference to synthetic wherein 1-(2,6-two chloro-3-fluorophenyls)-oxyethyl group compound exhibits that partly be pure (R)-isomer, and the compound exhibits of some to be the wherein said parts of reference be racemic mixtures.The program that it should be understood that this paper can be used to make racemic compound or enantiomeric pure (R) isomer through selecting the raw material of corresponding racemize or enantiomeric pure.

Select raw material

5-bromo-3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine (racemoid):

1. under 0 ℃, use ice bath, with 2, (150 milliliters, 0.5M) middle stirring is 10 minutes at THF for 6-two chloro-3-fluoro acetophenones (15 grams, 0.072 mole).Slowly add lithium aluminum hydride (2.75 grams, 0.072 mole).Reactant was stirred under envrionment temperature 3 hours.Reactant is cooled off in ice bath, and dropwise add water (3 milliliters), then add 15%NaOH (3 milliliters) at leisure.Mixture was stirred under envrionment temperature 30 minutes.Add 15%NaOH (9 milliliters), MgSO ₄, and filtering mixt, to remove solid.Solid is washed with THF (50 milliliters), and make filtrating concentrating, and get 1-(2,6-two chloro-3-fluoro-phenyl)-ethanol (14.8 grams, 95% yield), be yellow oil. ¹H?NMR(400MHz，DMSO-d6)δ1.45(d，3H)，5.42(m，2H)，7.32(m，1H)，7.42(m，1H)。

2. in triphenyl phosphine (8.2 grams; 0.03 the mole) with DEAD (13.65 milliliters, 40% solution in the toluene) in THF (200 milliliters) in stirred solution, under 0 ℃; Add 1-(2; 6-two chloro-3-fluoro-phenyl)-ethanol (4.55 grams, 0.021 mole) and the solution of 3-hydroxyl-nitropyridine (3.35 grams, 0.023 mole) in THF (200 milliliters).Formed bright orange solution was stirred 4 hours under nitrogen atmosphere and envrionment temperature, and this moment, all raw materials were consumed.Remove and to desolvate, and be filled on the silica gel crude material is dried, and with ETHYLE ACETATE-hexane (20: 80) wash-out, and produce 3-(2,6-two chloro-3-fluoro-benzyloxies)-2-nitro-pyridine (6.21 grams, 0.021 mole, 98%), be pink solid. ¹H?NMR(CDCl ₃，300MHz)δ1.8-1.85(d，3H)，6.0-6.15(q，1H)，7.0-7.1(t，1H)，7.2-7.21(d，1H)，7.25-7.5(m，2H)，8.0-8.05(d，1H)。

3. to through stir the mixture in suspension 3-(2,6-two chloro-3-fluoro-the benzyloxies)-2-nitro-pyridine (9.43 grams, 0.028 mole) and iron fragment (15.7 grams, 0.28 mole) of AcOH (650 milliliters) with EtOH (500 milliliters).To react and be heated to backflow at leisure, and it will be stirred 1 hour.Make reaction cooled to room temperature, add ether (500 milliliters) and water (500 milliliters) then.Through adding yellow soda ash, make the solution neutralization carefully.With the organic extract that merges with saturated NaHCO ₃(2x100 milliliter), H ₂O (2x100 milliliter) and salt solution (1x100 milliliter) washing, then dry (Na ₂SO ₄), filter, and under vacuum, be concentrated into driedly, and produce 3-(2,6-two chloro-3-fluoro-benzyloxies)-pyridine-2-base amine (9.04 grams, 0.027 mole, 99%), be rose pink solid. ¹H NMR(CDCl ₃，300MHz)δ1.8-1.85(d，3H)，4.9-5.2(brs，2H)，6.7-6.84(q，1H)，7.0-7.1(m，1H)，7.2-7.3(m，1H)，7.6-7.7(m，1H)。

4. utilize ice bath, make 3-(2,6-two chloro-3-fluoro-benzyloxies)-pyridine-2-base amine (9.07 grams, 0.03 mole) in acetonitrile, just be cooled to 0 ℃ at stirred solution.In this solution, N-bromine succinimide (NBS) (5.33 grams, 0.03 mole) is added in gradation.To be reflected at 0 ℃ stirred 15 minutes down.Make be reflected at be concentrated under the vacuum dried.Formed dark-coloured oil is dissolved among the EtOAc (500 milliliters), and through the silica gel chromatography purifying.Remove in a vacuum then and desolvate, and produce 5-bromo-3-(2,6-two chloro-3-fluoro-benzyloxies)-pyridine-2-base amine (5.8 grams, 0.015 mole, 51%), be the white crystalline solid. ¹H?NMR(CDCl ₃，300MHz)δ1.85-1.95(d，3H)，4.7-5.0(brs，2H)，5.9-6.01(q，1H)，6.8-6.95(d，1H)，7.01-7.2(t，1H)，7.4-7.45(m，1H)，7.8-7.85(d，1H)。

5-iodo-3-[1-(2,6-two chloro-3-fluoro-phenyl)-ethoxy pyridine-2-base amine (racemoid):

In 3-[1-(2,6-two chloro-3-fluoro-the phenyl)-oxyethyl group]-pyridine-solution of 2-base amine (10.0 grams, 33.2 mmoles) in acetonitrile (600 milliliters) and acetate (120 milliliters), add N-iodine succinimide (11.2 grams, 49.8 mmoles).Mixture was stirred under room temperature 4 hours, and with Na ₂S ₂O ₅Solution makes the reaction cancellation.After evaporation, residue is distributed between ETHYLE ACETATE and water.With organic layer with 2NNaOH solution, brine wash, and with Na ₂SO ₄Dry.Make crude product purifying on silicagel column, so that 5-iodo-3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine (7.1 grams, 50% yield) to be provided.MS?m/z?427[M+1]。 ¹HNMR(400MHz，DMSO-D6)δppm1.74(d，J＝6.57Hz，3H)5.91-5.99(m，3H)6.82(d，J＝1.26Hz，1H)7.46(t，J＝8.72Hz，1H)7.56(dd，J＝8.97，4.93Hz，1H)7.62(d，J＝1.52Hz，1H)。

5-bromo-3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group pyrazine-2-base amine (racemoid):

1. under 0 ℃, use ice bath, with 2, (150 milliliters, 0.5M) middle stirring is 10 minutes at THF for 6-two chloro-3-fluoro acetophenones (15 grams, 0.072 mole).Slowly add lithium aluminum hydride (deriving from Aldrich, 2.75 grams, 0.072 mole).To react under the envrionment temperature and stir 3 hours.Make to react in the ice bath and cool off, and dropwise add water (3 milliliters), then add 15%NaOH (3 milliliters) at leisure.Mixture was stirred under envrionment temperature 30 minutes.Add 15%NaOH (9 milliliters), MgSO ₄, and filtering mixt, to remove solid.Solid is washed with THF (50 milliliters), and make filtrating concentrating, and get 1-(2,6-two chloro-3-fluoro-phenyl)-ethanol (14.8 grams, 95% yield), be yellow oil. ¹HNMR(400MHz，DMSO-d ₆)δ1.45(d，3H)，5.42(m，2H)，7.32(m，1H)，7.42(m，1H)。

2.5-bromo-3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-base amine is made from 1-(2,6-two chloro-3-fluoro-phenyl)-ethanol and 3 according to hereinafter program 9,5-two bromo-pyrazine-2-base amine. ¹HNMR(400MHz，DMSO-d ₆)δ1.74(d，3H)，6.40(m，1H)，6.52(brs，2H)，7.30(m，1H)，7.48(m，1H)，7.56(s，1H)；MS?m/z?382(M+1)。

The raw material of enantiomeric pure

PLE is the enzyme of being made by Roche, and through biological catalyst company (Biocatalytics Inc), sells with the crude esterase prepared product that derives from pork liver, is commonly referred to as PLE-AS (available from biocatalysis company, selling with ammonium sulphate suspension with ICR-123).This enzyme is classified as " carboxylic ester hydrolase, CAS numbers 9016-1-6 " in the CAS registration.Its corresponding enzyme classification number is EC3.1.1.1.Known this enzyme has broad substrate specificity, to the hydrolysis of wide scope ester class.Lipase activity uses with the method that be hydrolyzed to basis of ethyl n-butyrate in the pH titrimeter and measures.1LU (lipase unit) is at 22 ℃, and under the pH8.2, PM discharges the titratable butyro-enzyme amount of 1 micromole.The prepared product (PLE-AS is suspension-s) of this place report is often with opaque breen transport of liquid, the activity of declaration＞45LU/ milligram (about 40 mg/ml of protein contnt).

(1S)-1-(2,6-two chloro-3-fluoro-phenyl) ethanol

Hereinafter in the scheme; (1S)-1-(2 with compound (S-1) demonstration; 6-two chloro-3-fluoro-phenyl) ethanol is enzymic hydrolysis, esterification and the chemical hydrolysis through racemize 1-(2,6-two chloro-3-fluoro-phenyl) ETHYLE ACETATE and process according to the combination of the reverse of option b.Racemize 1-(2,6-two chloro-3-fluoro-phenyl) ETHYLE ACETATE (compd A 2) is processed according to option A.

Option A

1-(2,6-two chloro-3-fluoro-phenyl) ethanol(A1): Peng Qinghuana (90 milligrams, 2.4 mmoles) is added into 2 ', 6 '-two chloro-3 '-(294-5) (207 milligrams, 1 mmole) are at 2 milliliters of anhydrous CH for Aldrich, catalogue #52 for the fluoro-methyl phenyl ketone ₃In the solution among the OH.Reaction mixture was at room temperature stirred 1 hour, evaporation then, and get the water white oil residue.Make residue pass through hurried chromatography purification (with the 0 → 10%EtOAc wash-out in the hexane), and get compd A 1, be (180 milligrams of water white oils; 0.88 mmole; 86.5% yield); MS (APCI) (M-H) ^-208; ¹HNMR (400MHz, the δ ppm 1.64 of chloroform-D) (d, J=6.82Hz, 3H) 3.02 (d, J=9.85Hz, 1H) 6.97-7.07 (m, 1H) 7.19-7.33 (m, 1H).

1-(2,6-two chloro-3-fluoro-phenyl) ETHYLE ACETATE(A2): diacetyl oxide (1.42 milliliters, 15 mmoles) and pyridine (1.7 milliliters, 21 mmoles) one after the other are added into compd A 1 (2.2 grams, 10.5 mmoles) at 20 milliliters of CH ₂Cl ₂In solution in.Reaction mixture was at room temperature stirred 12 hours, evaporation then, and must be with the yellow oil residue.Making residue pass through hurried chromatography purification (with the 7 → 9%EtOAc wash-out in the hexane), and get compd A 2, is water white oil (2.26 grams; 9.0 mmole; 85.6% yield); ¹H NMR (400MHz, the δ ppm1.88 of chloroform-D) (d, J=6.82Hz, 3H) 2.31 (s, and 3H) 6.62 (q, J=6.82Hz, 1H) 7.25 (t, J=8.46Hz, 1H) 7.49 (dd, J=8.84,5.05Hz, 1H).

Option b

In be equipped with pH electrode, on put whisking appliance and alkali and add 50 milliliters of pipeline (1MNaOH) and have in the flask of chuck, add 1.2 milliliters of 100mM potassium phosphate buffer pH7.0 and 0.13 milliliter of PLEAS suspension-s.Then, dropwise add compd A 2 (0.13 gram, 0.5 mmole, 1.00 equivalents), and formed mixture was stirred under room temperature 20 hours, use 1MNaOH, make reaction pH value keep being constant at 7.0.Transformation efficiency and the enantiomeric excess (ee) of reaction is worth both monitors through RP-HPLC, and after 50% raw material is consumed, stops (under these conditions, about 17 hours).Then, with mixture with 10 milliliters of ethyl acetate extractions three times, with reclaim ester and alcohol both, be the mixture of R-1 and S-2.

Under nitrogen atmosphere, methane sulfonyl chloride (0.06 milliliter, 0.6 mmole) is added in the solution of mixture (0.48 mmole) in 4 milliliters of pyridines of R-1 and S-2.Reaction mixture was at room temperature stirred 3 hours, and evaporation then obtains oil.Water (20 milliliters) is added in the mixture, then adds EtOAc (20 milliliters of x2) with extraction water solution.Merge organic layer, drying is filtered, and evaporation, and gets the mixture of R-3 and S-2.This mixture is used in the next step reaction, is not further purified. ¹H NMR (400MHz, δ ppm 1.66 (d, J=7.1Hz, 3H) 1.84 (d, the J=7.1Hz of chloroform-D); 3H) 2.09 (s, 3H) 2.92 (s, 3H) 6.39 (q, J=7.0Hz, 1H) 6.46 (q; J=6.8Hz, 1H) 6.98-7.07 (m, 1H) 7.07-7.17 (m, 1H) 7.23-7.30 (m; 1H) 7.34 (dd, J=8.8,4.80Hz, 1H).

Under nitrogen atmosphere, potassium acetate (0.027 gram, 0.26 mmole) is added in R-3 and the mixture of S-2 (0.48 mmole) in 4 milliliters of DMF.Reaction mixture is heated to 100 ℃, went through 12 hours.Water (20 milliliters) is added in the reaction mixture, and adds EtOAc (20 milliliters of x2) with extraction water solution.Make the organic layer of merging dry, filter, and evaporation, and the oily matter (72 milligrams, 61% yield is in two steps) of S-2.Chirality enantiomeric excess: 97.6%. ¹HNMR (400MHz, the δ ppm1.66 of chloroform-D) (d, J=7.1Hz, 3H) 2.09 (s, 3H) 6.39 (q, J=6.8Hz, 1H) 7.02 (t, J=8.5Hz, 1H) 7.22-7.30 (m, 1H).

Under nitrogen atmosphere and 0 ℃, with sodium methylate (19 mmoles; 0.5M, in methyl alcohol) slowly be added in the compound S-2 (4.64 grams, 18.8 mmoles).Formed mixture was stirred under room temperature 4 hours.Evaporating solvent, and add H ₂O (100 milliliters).Make chilled reaction mixture be neutralized to pH7 with sodium acetate-acetic acid buffer solution.Add ETHYLE ACETATE (100 milliliters of x2) with extraction water solution.The organic layer that makes merging is with Na ₂SO ₄Drying is filtered, and evaporation, to obtain white solid (4.36 grams, 94.9% yield); The SFC-MS:97% enantiomeric excess. ¹HNMR (400MHz, the δ ppm 1.65 of chloroform-D) (d, J=6.8Hz, 3H) 5.58 (q, J=6.9Hz, 1H) 6.96-7.10 (m, 1H) 7.22-7.36 (m, 1H).

3-[(1R)-1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group]-the 2-nitropyridine

Under nitrogen atmosphere; 3-hydroxyl-2-nitropyridine (175 milligrams, 1.21 mmoles) and triphenyl phosphine (440 milligrams, 1.65 mmoles) one after the other are added into (1S)-1-(2; 6-two chloro-3-fluoro-phenyl) ethanol (229.8 milligrams, 1.1 mmoles) in THF (10 milliliters) in stirred solution.Reaction mixture was at room temperature kept 1 hour, under 0 ℃, add azo-group-dicarboxylicacid diisopropyl ester (0.34 milliliter, 1.65 mmoles) then.With mixture restir 12 hours.Make the reaction mixture vaporising under vacuum, and get oily matter.Make residue pass through hurried chromatography purification (with the 20 → 25%EtOAc wash-out in the hexane), and get title compound, be (321.5 milligrams of white solids; 0.97 mmole; 88.3% yield); MS (APCI) (M+H) ⁺331; The SFC-MS:99.5% enantiomeric excess. ¹HNMR (400MHz, δ ppm1.85 (d, J=6.6Hz, 3H) 6.10 (q, J=6.6Hz, 1H) 7.04-7.13 (m, 1H) 7.21 (dd of chloroform-D); J=8.5,1.14Hz, 1H) 7.30 (dd, J=9.0,4.9Hz, 1H) 7.37 (dd; J=8.6,4.6Hz, 1H) 8.04 (dd, J=4.6,1.3Hz, 1H).

3-[(1R)-and 1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group] pyridine-2-amine

Under 0 ℃, with iron (365 milligrams) be added into 3-[(1R)-1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group]-2-nitropyridine (321 milligrams, 0.97 mmole) in the mixture of EtOH (2 milliliters) and 2MHCl (0.2 milliliter) in stirred solution.Formed solution is heated to 85 ℃, went through 2 hours.Zeyssatite (Celite) (0.5 gram) is added in the chilled reaction mixture.This mixture is filtered on bed of diatomaceous earth, and evaporation, and get title compound, be dark-coloured oil.MS(APCI)(M+H) ⁺301。

5-bromo-3-[1 (R)-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine:

It is said about racemoid that enantiomeric pure R isomer is pressed preceding text, but use the raw material of above-mentioned enantiomeric pure to process. ¹HNMR(400MHz，DMSO-d ₆)δ1.74(d，3H)，6.40(m，1H)，6.52(brs，2H)，7.30(m，1H)，7.48(m，1H)，7.56(s，1H)；MSm/z382(M+1)。

5-iodo-3-[(R) 1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine:

Periodic acid 99 (60 milligrams, 0.24 mmole), iodine (130 milligrams, 0.5 mmole) and sulfuric acid (0.03 milliliter) one after the other are added into 3-[(1R)-1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group] pyridine-2-amine (0.97 mmole) at acetate (3 milliliters) and H ₂In the mixture of O (0.5 milliliter) in stirred solution.Formed solution is heated to 80 ℃, went through 5 hours.With Na ₂SO ₃(80 milligrams) make chilled reaction mixture cancellation, and with saturated Na ₂CO ₃(2x100 milliliter) alkalizes to pH7.Add CH ₂Cl ₂(2x50 milliliter) is with extraction water solution.The organic layer that makes merging is with Na ₂SO ₄Drying is filtered then, and under vacuum, concentrates.Make residue pass through hurried chromatography purification (with the 35 → 40%EtOAc wash-out in the hexane), and get title compound, be (254 milligrams of yellow oils; 0.6 mmole; 61.6% yield); MS (APCI) (M+H) ⁺426. ¹HNMR (400MHz, δ ppm1.81 (d, J=6.8Hz, 3H) 4.86 (s, 2H) 5.98 (q, the J=6.57Hz of chloroform-D); 1H) 6.96 (d, J=1.5Hz, 1H) 7.08 (dd, J=9.0,8.0Hz, 1H) 7.31 (dd; J=8.8,4.8Hz, 1H) 7.78 (d, J=1.8Hz, 1H).

5-bromo-3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-base amine:

Title compound is made from (1S)-1-(2,6-two chloro-3-fluorophenyls) ethanol according to program 2. ¹HNMR(400MHz，DMSO-d6)δ7.53(s，1H)，7.48(m，1H)，7.39(t，1H)，6.48(s，2H)，6.41(q，1H)，1.74(d，3H)；LCMS：381[M+1]；c-MetKi：0.796μM。

General procedure 1

Make 1-(uncle-butoxy carbonyl) azetidine-3-carboxylic acid ( 1-1) (AXL016917,1000 milligrams, 4.97 mmoles) be dissolved in MeOH (5 milliliters)/toluene (20 milliliters), is cooled to 0 ℃ then.Then dropwise add TMSCHNN (trimethylsilyldiazomwhiche whiche) (7.45 mmole), go through 15 minutes, and find a little foaming.Color begins transparent, and slowly is transformed into yellow.Solution was stirred 10 minutes down at 0 ℃, be warmed to room temperature then, went through 30 minutes.Make solution concentration then, and pumping obtains 1.055 gram 3-methyl azetidines-1 removing toluene, 3-dicarboxylicacid uncle 1--butyl ester ( 1-2), it directly is used in the next step, there is not purifying (99% thick yield).

Make 3-methyl azetidine-1,3-dicarboxylicacid uncle 1--butyl ester (1055 milligrams, 4.90 mmoles) is dissolved among the THF (17 milliliters), is cooled to 0 ℃ then.One after the other add MeOH (0.397 milliliter, 9.80 mmoles) and LiBH ₄(14.7 mmole).Make reaction be warmed to room temperature, went through 3 hours.Then add the 10% Seignette salt tetrahydrate aqueous solution (RochelleShi salt) (30 milliliters) and EtOAc (30 milliliters), and solution was stirred under room temperature 30 minutes.Separate organic layer, dry then (Na ₂SO ₄), and concentrate, and 674 milligrams of 3-(methylol) azetidine-1-carboxylic acid uncle-butyl ester ( 1-3), be crude product (clean oil).Product directly is used in next step, does not have purifying.

Make 3-(methylol) azetidine-1-carboxylic acid uncle-butyl ester (674 milligrams, 3.60 mmoles) be dissolved in CH ₂Cl ₂(13 milliliters, 0.25M) in, under 0 ℃, one after the other add Et then ₃N (1.0 milliliters, 7.20 mmoles), DMAP (44 milligrams, 0.360 mmole) and methane sulfonyl chloride (0.31 milliliter, 3.96 mmoles), and add MsCl at leisure.Make solution be warmed to room temperature, went through 1 hour.After 15 hours, add saturated NaHCO ₃The aqueous solution (50 milliliters) is followed product with CH ₂Cl ₂(2x50 milliliter) extracts, and the organic extract that merges is washed with salt solution (50 milliliters), dry (Na ₂SO ₄), concentrate, and through hurried chromatography purification (BiotageHorizon-10%EtOAc/ hexane-100%EtOAc), and 962 milligrams ( 1-4), be oily matter (quantitatively).

At N ₂And under the room temperature, NaH (95%, 96 milligram, 3.99 mmoles) is merged in DMF (10 milliliters).Then, add 4-bromine pyrazoles (533 milligrams, 3.63 mmoles), and mixture is stirred under room temperature.After 30 minutes, add ( 1-4), and solution is heated to 95 ℃.After 2 hours, add saturated NH ₄The Cl aqueous solution (50 milliliters) then adds EtOAc (50 milliliters).Make the dry (Na of organic extract ₂SO ₄), and concentrate, then through too short silica gel pad, carry out with the 50%EtOAc/ hexane, and 846 milligrams rough ( 1-5), it directly is used in the next step (74% thick yield).

Will ( 1-5) (846 milligrams, 2.68 mmoles), ( 1-6) (815 milligrams, 3.21 mmoles), [1,1 '-two (diphenylphosphino)-ferrocene) dichloro palladium (108 milligrams, 0.133 mmole) and KOAc (893 milligrams, 9.10 mmoles), DMSO (10 milliliters, with N ₂Purged 10 minutes) the middle merging, make solution be warmed to 80 ℃ then.After 16 hours, make solution, then add H through diatomite filtration ₂O (50 milliliters) and EtOAc (50 milliliters).With organic extractant phase, and dry (Na ₂SO ₄), concentrate, then through unmodified packed column, use the 50%EtOAc/ hexane.Solvent is concentrated, and the rough thing of 1.22 grams ( 1-7), it directly is used in the next step.

With dihydroxyl borine (boronic) ester ( 1-7) (4144 milligrams, 11.4 mmoles), ( 1-8) two (triphenyl phosphine) palladiums (II) (534 milligrams, 0.760 mmole) of (2890 milligrams, 7.60 mmoles), dichloro, DME (40 milliliters, with N ₂Outgased 30 minutes) and 1N Na ₂CO ₃(40 milliliters, with N ₂Outgased 30 minutes) merge, and be heated to 80 ℃.After 16 hours, make reaction cooled, and add EtOAc (80 milliliters) to room temperature.Make solution through diatomite filtration, then add water (80 milliliters).Separate organic layer, dry (Na ₂SO ₄), and concentrate.Make product pass through hurried chromatography purification, and 1486 milligrams ( 1-9), be tawny solid (36%).

1 gram DOWEX 50WX2-400 ion exchange resin passes through it with H ₂O (500 milliliters), 1: 1H ₂O/MeOH, MeOH (5x250 milliliter), CH ₂Cl ₂(500 milliliters) and hexane (500 milliliters) wash and process.Then, make DOWEX in vacuum drying oven, drying is 1 day under 40 ℃.Make ( 1-9) be dissolved among the MeOH, then add DOWEX (588 milligrams, 1.096 mmoles).This solution was at room temperature stirred 2 hours.Filtering solution then, and with resin with MeOH (3x200 milliliter) washing, and abandon washing lotion.Follow resin with 3.5MNH ₃/ MeOH washing, and collect.Make solution concentration then, and 374 milligrams ( 1-10), be gluing solid (78%).

Can be according to following program of giving an example, with form formula ( 1-11) compound.Make 1 molar equivalent ( 1-10) be dissolved in DMF or CH ₂Cl ₂In, add alkali (3 molar equivalent) and/or coupling reagent (1.5 molar equivalent) then.In this solution, add X-R (1.1 molar equivalent), wherein X is for example Cl, Br, I, OMs, COCl, CO, COOH, ethene or carbonic ether, and R is desired group, for example person shown in this paper embodiment, or similar group.Formed solution was at room temperature stirred 4 hours.Add H ₂O and EtOAc, and extracted organic phase, dry (Na ₂SO ₄), and concentrate.Crude product can pass through preparation HPLC or other method purifying well known in the art, and product ( 1-11).

General procedure 2

3-azetidin alkanol ( 2-2): make N-dibenzo-p-methyl-aza-cyclobutane-3-alcohol HCl salt (2.76 grams, 10.0 mmoles) and palladium hydroxide, 20%Pd (butt) on C (400 milligrams), the reaction mixture in 50 milliliters of MeOH, hydrogenation is 48 hours under 55psi.Reaction mixture is filtered through Celite pad, and with the MeOH thorough washing.Make and filtrate under vacuum, in room-temperature water bath, concentrate.Residue is handled with ether (3x30 milliliter), and with the solvent decant.Air-dry solid, and 571 milligrams of HCl salt products ( 2-2), be white solid (52% yield). ¹HNMR(400MHz，DMSO-D6)δppm 3.33(s，1H)3.63-3.80(m，2H)3.93-4.09(m，2H)4.40-4.58(m，1H)6.18(d，J＝6.32Hz，1H)。

3-hydroxyl-azetidine-1-carboxylic acid uncle-butyl ester ( 3-3): in compound ( 2-2) (570 milligrams, 5.20 mmoles) cold (0 ℃ of bath) in 10 milliliters of EtOH in stirred solution, add Et ₃N (1.8 milliliters, 13.0 mmoles) and two carbonic acid di-tert-butyls (1.702 grams, 7.38 mmoles).With formed clear solution mixture stirred overnight under room temperature.Make reaction mixture pass through vacuum concentration.Residue is distributed between EtOAc (200 milliliters) and 0.5N citric acid solution (30 milliliters), salt solution (30 milliliters).Make the dry (Na of organic layer ₂SO ₄), then through vacuum concentration, and 899 milligrams ( 2-3), be clean oil (52%). ¹HNMR (400MHz, the δ ppm 1.42 of chloroform-D) (s, 9H) 3.78 (dd, J=9.47,4.42Hz, 2H) 4.13 (dd, J=9.35,6.57Hz, 2H) 4.49-4.63 (m, 1H).

3-methanesulfonyloxy group-azetidine-1-carboxylic acid uncle-butyl ester ( 2-4): in compound ( 2-3) (466 milligrams; 2.69 mmole) and Et ₃(0.75 milliliter of N; 5.38 mmole) and 4-(dimethylamino)-pyridine (33 milligrams, 0.269 mmole) at 10 milliliters of CH ₂Cl ₂In solution in, under 0 ℃, add methane sulfonyl chloride (0.25 milliliter, 3.23 mmoles).With formed brown solution mixture 0 ℃ of stirred overnight to the room temperature.With NaHCO ₃Make the reaction mixture cancellation, then in CH ₂Cl ₂(200 milliliters) and saturated NaHCO ₃Distribute between the solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), then filter through silicagel pad, with hexane: EtOAc/1: 1 wash-out, making filtrating through vacuum concentration, and 614 milligrams ( 2-4), be yellow oil (91% yield). ¹HNMR (400MHz, the δ ppm 1.43 of chloroform-D) (s, 9H) 3.05 (s, 3H) 4.08 (dd, J=10.36,4.29Hz, 2H) 4.26 (dd, J=10.36,6.82Hz, 2H) 5.11-5.26 (m, 1H).

1-(3-azetidine-1-carboxylic acid uncle-butyl ester)-4-bromine pyrazoles ( 2-6): in 5 milliliters of microwave pipe fittings, load compound ( 2-4) (304 milligrams, 1.21 mmoles); 4-bromine pyrazoles ( 2-5, 178 milligrams, 1.21 mmoles) and Dormant oils in 60%NaH (73 milligrams, 1.82 mmoles) and 2 milliliters of DMF.With formed mixture in 110 ℃ of following microwaves 30 minutes.Make reaction mixture in EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (2x50 milliliter), the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), then through vacuum concentration, and 360 milligrams ( 2-6), be yellow oil (98%). ¹HNMR(400MHz，DMSO-D6)δppm?1.36-1.43(m，9H)4.08(s，2H)4.18-4.31(m，2H)5.12-5.22(m，1H)7.67(s，1H)8.14(s，1H)。

3-[4-(4,4,5,5-tetramethyl--1,3-dioxo ring pentaborane-2-yl)-1H-pyrazol-1-yl] azetidine-1-carboxylic acid uncle-butyl ester ( 2-8): with compound ( 2-6) (225 milligrams, 0.74 mmole) and two (which acid esters (Pinacolate) frequently) two boron ( 2-7, 227 milligrams, 0.89 mmole) and the reaction mixture of KOAc (247 milligrams, 2.52 mmoles) in 3 milliliters of DMSO, with N ₂Purged 15 minutes, and added PdCl then ₂(dppf) ₂CH ₂Cl ₂(30 milligrams, 2.52 mmoles).With formed mixture in 80 ℃ and N ₂Following stirred overnight.After it is cooled to room temperature, mixture is filtered through Celite pad, and with the EtOAc thorough washing.To filtrate with H ₂O (2x50 milliliter), salt solution (50 milliliters) extraction.Make the dry (Na of organic layer ₂SO ₄), pass through vacuum concentration then.Residue is filtered, with hexane: EtOAc/3: 2 wash-outs through silicagel pad.Making filtrating through vacuum concentration, and 250 milligrams ( 2-8), be clean oil (97% yield). ¹HNMR (400MHz, the δ ppm1.18-1.27 of chloroform-D) (m, 9H) 1.28-1.34 (m, 6H) 1.41-1.49 (m, 6H) 4.22-4.33 (m, 2H) 4.36 (t, J=8.59Hz, 2H) 4.98-5.13 (m, 1H) 7.83 (s, 2H).

3-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) azetidine-1-carboxylic acid uncle-butyl ester ( 2-10): with compound ( 2-8) (459 milligrams; 1.31 mmole) with 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-iodine pyridine-2-amine ( 2-9) (374 milligrams; 0.88 the reaction mixture in 13 milliliters of anhydrous ethylene glycol dimethyl ether (DME) mmole) is with N ₂Purged 15 minutes, and added Pd (II) (PPh then ₃) ₂Cl ₂(46 milligrams, 0.07 mmole), and continue with N ₂Purged again 15 minutes.With N ₂Purge after 15 minutes, add another part 1.0N Na ₂CO ₃(3.9 milliliters of solution; 3.9 mmole).With formed mixture in 85 ℃ and N ₂Following stirred overnight.Reaction mixture is filtered through Celite pad, and with the MeOH thorough washing.Filtrating is concentrated by vacuum.Make residue in EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (2x50 milliliter), the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), pass through vacuum concentration then.Make residue pass through Biotage system (25M, 100%CH ₂Cl ₂100%CH ₂Cl ₂To 90%CH ₂Cl ₂, have 10%MeOH) purifying, collect desired level and divide, and 421 milligrams ( 2-10), be brown grease (92% yield). ¹HNMR (400MHz, δ ppm 1.17-1.26 (m, 9H) 1.80-1.87 (m, 3H) 4.04-4.18 (m, 2H) 4.20-4.33 (m of chloroform-D); 2H) 4.34-4.41 (m, 1H) 4.79 (s, 2H) 5.02 (d, J=7.58Hz; 1H) 7.04 (t, J=8.46Hz, 1H) 7.33-7.41 (m, 1H) 7.44-7.52 (m; 1H) 7.53-7.58 (m, 1H) 7.59-7.65 (m, 1H) 7.72-7.78 (m, 1H); To C ₂₄H ₂₆Cl ₂FN ₅O ₃(M+H) LCMS calculated value 523, measured value 523.

5-(1-azetidine-3-base-1H-pyrazoles-4-yl)-3-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group] pyridine-2-amine ( 2-11): with compound ( 2-10) (421 milligrams; 0.81 mmole) with two

(2.0 milliliters of 4.0M HCl in the alkane; 8.1 mmole) at 5 milliliters of CH ₂Cl ₂In reaction mixture, under room temperature, stirred 2.0 hours.Make reaction mixture pass through vacuum concentration.Residue is handled with EtOAc.Settled solid is leached, and with EtOAc, hexane thorough washing, dry under vacuum then, and 275 milligrams ( 2-11), be the sand look solid (81% yield) of HCl salt. ¹HNMR(400MHz，DMSO-D6)δppm1.79-1.89(m，3H)3.56(s，1H)4.35(s，4H)5.40(s，1H)6.23(d，J＝6.57Hz，2H)7.09(s，1H)7.40-7.54(m，1H)7.59(dd，J＝8.84，5.05Hz，1H)7.73-7.83(m，1H)7.86(s，1H)8.12(s，1H)9.20(s，1H)。To C ₁₉H ₁₈Cl ₂FN ₅The LCMS calculated value 423 of O (M+H), measured value 423.

Formula 2-12Compound can be processed through following program of giving an example: in compound ( 2-11) (1.0 equivalent) and Et ₃In the reaction mixture of N (2.0 equivalent) in 2.0 milliliters of DMF, at room temperature, add alkyl bromide (1.1 equivalent).With formed mixture in N ₂And stirred overnight under the room temperature.Make reaction mixture in EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (2x50 milliliter), the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), pass through vacuum concentration then.(5% to 95%MeCN:H to make residue pass through the Dionex system ₂O w 0.1%HOAc damping fluid) purifying is collected desired level and is divided, and get ( 2-12).

Perhaps, formula 2-12Compound can be processed through following program of giving an example: in alkylamine (1.0 equivalent) and iPr ₂In the reaction soln of EtN (diisopropylethylamine) (3.0 equivalent) in 2.0 milliliters of DMF, add HATU (1.5 equivalent).After stirring 30 minutes, the interpolation compound ( 2-11) (1.0 equivalent).With formed mixture stirred overnight under room temperature.Make reaction mixture in EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (2x50 milliliter) and the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), and pass through vacuum concentration.(5% to 95%McCN:H to make residue pass through the Dionex system ₂O w 0.1%HOAc) purifying is collected desired product, and get ( 2-12).

General procedure 3:

1-oxa--6-azaspiro [2.5] octane-6-carboxylic acid uncle-butyl ester ( 3-2): the solution of dimethyl-oxidation sulfonium methide is in N ₂Down, NaH 60% dispersion-s in Dormant oils of system in 5 milliliters of anhydrous DMSO is (440 milligrams; 11.0 mmole) with iodate trimethylammonium sulfoxonium (2.421 grams; 11.0 mmole).Dropwise add 1-Boc-4-oxo-1-piperidine carboxylic acid ( 3-1, 1.993 grams; 10.0 the another kind of solution in 5 milliliters of DMSO mmole).Formed mixture was stirred 6 hours down in 55 ℃.Pour chilled reaction mixture into ice-H ₂Among the O, and extract with EtOAc (2x200 milliliter).With the organic layer that merges with H ₂O (50 milliliters), salt solution (50 milliliters) washing, dry then (Na ₂SO ₄), then through vacuum concentration, and 1.4791 grams ( 3-2), be yellow oil (69% yield). ¹HNMR (400MHz, the δ ppm1.37-1.52 of chloroform-D) (m, 11H) 1.71-1.84 (m, 2H) 2.63-2.72 (m, 2H) 3.35-3.49 (m, 2H) 3.62-3.78 (m, 2H).

4-hydroxyl-4-{ [4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl] methyl } piperidines-1-carboxylic acid uncle-butyl ester ( 3-4): with compound ( 3-2) (214 milligrams; 1.0 mmole) and 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles ( 3-3, 194 milligrams; 1.0 mmole) with (60 milligrams of 60% dispersion-s of NaH in Dormant oils; 1.5 the reaction mixture in 3 milliliters of DMF mmole) stirred 3 hours down in 90 ℃.Make reaction mixture in EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (50 milliliters) and the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), and through vacuum concentration, and 361 milligrams ( 3-4), be yellow grease (89% yield). ¹HNMR (400MHz, the δ ppm1.21-1.34 of chloroform-D) (m, 12H) 1.39-1.50 (m, 9H) 1.56-1.78 (m, 4H) 3.14. (s, 2H) 3.72-3.91 (m, J=32.34Hz, 2H) 4.05 (s, 2H) 7.65 (s, 1H) 7.80 (s, 1H) 8.00 (s, 1H).To C ₂₀H ₃₄BN ₃O ₅(M+H) LCMS calculated value 408, measured value 408.HPLC purity 85%.

4-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl]-4-hydroxy piperidine-1-carboxylic acid uncle-butyl ester ( 3-6): with compound ( 3-4) (361 milligrams; 0.89 mmole) with 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-iodine pyridine-2-amine ( 3-5) (378 milligrams; 0.89 the reaction mixture in 9.0 milliliters of anhydrous ethylene glycol dimethyl ether (DME) mmole) is with N ₂Purged 15 minutes, and added Pd (II) (PPh then ₃) ₂Cl ₂(32 milligrams, 0.05 mmole), and continue with N ₂Purged again 15 minutes.Add another part 1.0N Na ₂CO ₃(3.9 milliliters of solution; 3.9 mmole), then with N ₂Purged 15 minutes.With formed mixture in 85 ℃ and N ₂Following stirred overnight.Reaction mixture is filtered through Celite pad, and with the MeOH thorough washing.Filtrating is concentrated by vacuum.Make residue in EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (2x50 milliliter), the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), pass through vacuum concentration then.(25% to 95%MeCN:H to make residue pass through the Dionex system ₂O w 0.1%HOAc damping fluid) purifying is collected desired level and is divided, and 147 milligrams ( 3-6), be white solid (28% yield). ¹HNMR(400MHz，DMSO-D6)δppm1.34-1.39(m，9H)1.70-1.77(m，2H)1.79(d，J＝6.57Hz，3H)3.06(d，J＝12.63Hz，2H)3.62(s，2H)4.03(s，2H)4.79(s，1H)5.66(s，2H)6.08(d，J＝6.82Hz，1H)6.86(d，J＝1.52Hz，1H)7.44(t，J＝8.72Hz，1H)7.51-7.58(m，2H)7.58-7.65(m，2H)7.73(d，J＝1.52Hz，1H)7.78(s，1H)。To C ₂₇H ₃₂Cl ₂FN ₅O ₄(M+H) LCMS calculated value 581, measured value 581.HPLC purity 87%.

4-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl] piperidines-4-alcohol ( 3-7): with compound ( 3-6) (145 milligrams; 0.25 mmole) with two

(2.0 milliliters of 4.0M HCl in the alkane; 8.1 mmole) at 5 milliliters of CH ₂Cl ₂In reaction mixture, under room temperature, stirred 2.0 hours.Make reaction mixture pass through vacuum concentration.(5% to 95%MeCN:H to make residue pass through the Dionex system ₂O w 0.1%HOAc damping fluid) purifying is collected desired level and is divided, and 76 milligrams ( 3-7), be yellow grease (63% yield). ¹HNMR(400MHz，DMSO-D6)δppm1.41-1.55(m，2H)1.59-1.71(m，2H)1.81(d，J＝6.57Hz，3H)2.88-3.00(m，2H)3.02-3.14(m，2H)4.08(s，2H)5.17(s，2H)6.14-6.27(m，J＝6.57Hz，1H)7.05(s，1H)7.40-7.49(m，J＝8.72，8.72Hz，1H)7.51-7.60(m，J＝9.09，4.80Hz，1H)7.63(s，1H)7.76(s，1H)7.91(s，1H)8.51(s，1H)8.81(s，1H)。To C ₂₂H ₂₄Cl ₂FN ₅O ₂(M+H) LCMS calculated value 481, measured value 481.HPLC purity 98%.Analyze (C ₂₂H ₂₄Cl ₂FN ₅O ₂X2.2HOAcx 2.3H ₂O) C, H, N.

General procedure 4:

2-[(4-bromo-1H-pyrazol-1-yl) methyl] cyclopropane carboxylic acid acetoacetic ester ( 4-3): in 2-(methylol) cyclopropane carboxylic acid acetoacetic ester ( 4-1) (577 milligrams; 4.0 mmole) and Et ₃(1.1 milliliters of N; 8.0 mmole) and (49 milligrams of DMAP; 0.4 mmole) at 12 milliliters of CH ₂Cl ₂In reaction soln in, under 0 ℃, add (0.4 milliliter of methane sulfonyl chloride; 4.8 mmole).With the mixture of formation brown suspension-s at 0 ℃ to room temperature and N ₂Following stirred overnight.With NaHCO ₃Make the reaction mixture cancellation, then in CH ₂Cl ₂(200 milliliters) and saturated NaHCO ₃Solution (50 milliliters); Distribute between the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), filter through silicagel pad then, with hexane: EtOAc/1: 1 wash-out, making filtrating through vacuum concentration, and 880 milligrams of 2-{ [(methylsulfonyl) oxygen base] methyl the cyclopropane carboxylic acid acetoacetic ester, be yellow oil (99% yield). ¹HNMR (400MHz, the δ ppm0.91-1.02 of chloroform-D) (m, 1H) 1.26 (q, J=6.99Hz, 3H) 1.29-1.36 (m, 1H) 1.63-1.74 (m, 1H) 1.79-1.92 (m, 1H) 3.02 (s, 3H) 3.99-4.24 (m, 4H).

Make 2-{ [(methylsulfonyl) oxygen base] methyl } (880 milligrams of cyclopropane carboxylic acid acetoacetic esters; 4.0 mmole), 4-bromine pyrazoles ( 4-2, 588 milligrams, 4.0 mmoles) and Dormant oils in the reaction mixture of 60%NaH (240 milligrams, 6.0 mmoles) and 3.0 milliliters of DMF form.With formed mixture in 90 ℃ and N ₂Under stirred four hours.Make reaction mixture in EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (2x50 milliliter), the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), then through vacuum concentration, and 812 milligrams ( 4-3), be yellow oil (74%). ¹HNMR (400MHz, δ ppm0.85 (dd, J=7.96,3.16Hz, 1H) 0.88-0.98 (m of chloroform-D); 1H) 1.18-1.29 (m, 3H) 1.56-1.71 (m, 1H) 1.79-1.94 (m, 1H) 3.96-4.08 (m; 2H) 4.07-4.17 (m, 2H) 7.45 (d, J=3.79Hz, 2H).To C ₁₀H ₁₃BrN ₂O ₂(M+H) LCMS calculated value 274, measured value 274.HPLC purity 95%.

2-{ [4-(4,4,5,5-tetramethyl--1,3-dioxo ring pentaborane-2-yl)-1H-pyrazol-1-yl] methyl } the cyclopropane carboxylic acid acetoacetic ester ( 4-4): with compound ( 4-3) (812 milligrams, 2.97 mmoles) and two (which acid esters frequently) two boron (906 milligrams, 3.57 mmoles) and the reaction mixture of KOAc (991 milligrams, 10.10 mmoles) in 10.0 milliliters of DMSO, with N ₂Purged 15 minutes, and added PdCl then ₂(dppf) ₂CH ₂Cl ₂(122 milligrams, 0.15 mmole).With formed mixture in 80 ℃ and N ₂Following stirred overnight.After being cooled to room temperature, mixture is filtered through Celite pad, and with the EtOAc thorough washing.To filtrate with H ₂O (2x50 milliliter), salt solution (50 milliliters) extraction.Make the dry (Na of organic layer ₂SO ₄), pass through vacuum concentration then.Residue is filtered through silicagel pad, and with hexane: EtOAc/3: 1 wash-out.Making filtrating through vacuum concentration, and 945 milligrams ( 4-4), be yellow oil (98% yield). ¹HNMR (400MHz, δ ppm0.85 (dd, J=7.83,3.03Hz, 1H) 0.90-0.96 (m of chloroform-D); 1H) 1.20-1.24 (m, 3H) 1.29-1.34 (m, 12H) 1.62-1.71 (m, 1H) 1.84-1.97 (m; 1H) 3.96-4.07 (m, 1H) 4.06-4.14 (m, 2H) 4.15-4.23 (m, J=14.27; 6.44Hz, 1H) 7.73 (s, and 1H) 7.77 (s, 1H).

2-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl] the cyclopropane carboxylic acid acetoacetic ester ( 4-6): with compound ( 4-4) (643 milligrams; 2.01 mmole) with 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-iodine pyridine-2-amine ( 4-5) (572 milligrams; 1.34 the reaction mixture in 20.0 milliliters of anhydrous ethylene glycol dimethyl ether (DME) mmole) is with N ₂Purged 15 minutes, and added Pd (II) (PPh then ₃) ₂Cl ₂(71 milligrams, 0.1 mmole), and continue with N ₂Purged again 15 minutes.With N ₂Purge after 15 minutes, add another part 1.0N Na ₂CO ₃(6.0 milliliters of solution; 6.0 mmole).With formed mixture in 85 ℃ and N ₂Following stirred overnight.Reaction mixture is filtered through Celite pad, and with the MeOH thorough washing.Filtrating is concentrated by vacuum.Make residue in EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (2x50 milliliter), the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), pass through vacuum concentration then.Make residue pass through the (25MCH of Biotage system ₂Cl ₂100%; CH ₂Cl ₂100% to 90%CH ₂Cl ₂: 10%MeOH) purifying, collect desired level and divide, and 600 milligrams ( 4-6), be brown grease (91% yield). ¹HNMR(400MHz，DMSO-D6)δppm0.96-1.10(m，2H)1.15(t，J＝7.07Hz，2H)1.74(s，3H)1.79(d，J＝6.57Hz，3H)3.95-4.14(m，4H)5.66(s，2H)6.08(d，J＝6.57Hz，1H)6.88(s，1H)7.43(t，J＝8.72Hz，1H)7.49-7.62(m，2H)7.73(s，1H)7.88(s，1H)。To C ₂₃H ₂₃Cl ₂FN ₄O ₃(M+H) LCMS calculated value 494, measured value 494.HPLC purity 95%.

2-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl] cyclopropane-carboxylic acid ( 4-7): in compound ( 4-6) in (377 milligrams, 0.76 mmole) reaction soln in 5.0 milliliters of MeOH, at room temperature and N ₂Under add the solution of another part 2.0NNaOH (2) (1.5 milliliters, 3.04 mmoles).Formed mixture was stirred 3 hours down at 80 ℃.Make reaction mixture pass through vacuum concentration, removing most of MeOH, and be acidified to pH4.0 through 2M HCl.With mixture with CH ₂Cl ₂(2x200 milliliter) extraction; Organic layer is washed with salt solution (50 milliliters), and dry (Na ₂SO ₄), and through vacuum concentration, and 324 milligrams ( 4-7), be yellow solid.(92% yield). ¹HNMR(400MHz，DMSO-D6)δppm0.92-1.04(m，2H)1.57-1.72(m，2H)1.76-1.90(m，3H)3.98-4.18(m，2H)6.46(s，2H)6.89-7.02(m，1H)7.29-7.52(m，2H)7.52-7.63(m，2H)7.73(d，J＝1.52Hz，1H)7.94(s，1H)12.19(s，1H)。To C ₂₁H ₁₉Cl ₂FN ₄O ₃(M-H) LCMS calculated value 463, measured value 463.HPLC purity 87%.

2-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl]-N-methyl cyclopropane carboxylic acid amides ( 4-8) (R=Me, R '=H): in ( 4-7) (1.0 equivalent) and iPr ₂In the reaction soln of EtN (2.0 equivalent) in 1.0 milliliters of DMF, add HATU (1.5 equivalent).After stirring 30 minutes, add alkylamine (1.1 equivalent).With formed mixture stirred overnight under room temperature.Make reaction mixture in EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (2x50 milliliter) and the salt solution (50 milliliters).Make the dry (Na of organic layer ₂SO ₄), and pass through vacuum concentration.Through making sample at EtOAc (200 milliliters) and saturated NaHCO ₃Distribute between solution (50 milliliters) and the salt solution (50 milliliters), and free alkalization.Make the dry (Na of organic layer ₂SO ₄), and pass through vacuum concentration.With residue with 1.0 milliliters of H ₂O handles, and freeze-drying, and get ( 4-8).

General procedure 5:

In 4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-1H-pyrazoles (5 grams, 25.77 mmoles) and the solution of 2-bromo-2-methyl-methyl propionate (12.6 grams, 27.06 mmoles) in DMF (85 milliliters), add Cs ₂CO ₃(12.6 grams, 38.65 mmoles).Reaction mixture is heated to 90 ℃ in oil bath spend the night.Make reaction soln be cooled to room temperature, and between water and ETHYLE ACETATE, distribute.With the ethyl acetate solution that merges with water washing five times, with Na ₂SO ₄Drying, and concentrate, and get product 2-methyl-2-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-pyrazol-1-yl] methyl propionate (4.776 grams, 63% yield).

In 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-iodo-pyridine-[4-(4 with 2-methyl-2-for 2-base amine (6.363 grams, 14.901 mmoles); 4,5,5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-pyrazol-1-yl] in the solution of methyl propionate (4.6 gram, 15.64 mmoles) in DME (27 milliliters); Add the solution of CsF (6.79 grams, 44.7 mmoles) in water (9.3 milliliters).Make reaction mixture with N ₂Outgas 3 times.Add Pd (dppf) CH ₂Cl ₂, and make reaction mixture with N ₂Outgas 3 times.To react on and be heated to 120 ℃ (with 30 minutes intervals, then adding Pd, till reaction is accomplished) in the microwave.Add water, and will react extraction, with Na with EtOAc ₂SO ₄Drying, and concentrate, and 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-2-methyl-methyl propionate.Make crude product pass through silica gel column chromatography; Use 25%-50%EtOAc/ hexane gradient purifying, 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-2-methyl-methyl propionate (1.46 grams are provided; 21% yield), has R _f(0.11 50%EtOAc/ hexane).

In the solution of methyl esters (2.92 grams, 6.25 mmoles) in MeOH (31 milliliters), add the solution of LiOH (450 milligrams, 18.76 mmoles) in water (6.25 milliliters).Reaction is heated to 60 ℃, shows complete hydrolysis (about 45 minutes) up to LCMS.In vacuum, remove MeOH, and add MeOH (2.5 milliliters) and water (1 milliliter).The pH value is adjusted to pH5 with 1N HCl, and wherein deposition is separated out product.After filtering, acquisition 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-2-methyl-propionic acid product (2.825 grams, quantitatively).

In the solution of 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-2-methyl-propionic acid (1.00 grams, 2.20 mmoles) in DMF (5.5 milliliters); Add (300 milligrams of HOBT; 2.20 mmole), EDC (633 milligrams, 3.30 mmoles) and N, N-dimethyl--propane-1; 3-diamines (225 milligrams, 2.20 mmoles).To react stirred overnight at room temperature.Make reaction through anti-phase C-18 preparation HPLC purifying then; To have the acetonitrile/water wash-out of 0.1% acetate; ([1-(2 for 4-{6-amino-5-and get 2-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(3-dimethylamino-propyl group)-isobutyramide (170 milligrams, 14% yield).

General procedure 6:

In 5-bromo-3-[(R)-1-(2; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine (12.83 grams; 33.76 mmole) in the solution in dry DMF (100 milliliters); Add two carbonic acid di-tert-butyls (21.25 grams, 97.35 mmoles) and 4-Dimethylamino pyridine (0.793 gram, 6.49 mmoles).To react under envrionment temperature and the nitrogen and stir 18 hours.In mixture, add saturated NaHCO ₃Solution (300 milliliters), and extract with EtOAc (3x250 milliliter).With the extract that merges with water (5x100 milliliter), saturated NaHCO ₃And brine wash, then with Na ₂SO ₄Dry.After filtration, evaporation and high vacuum dry, the 5-bromo-3-of acquisition two-boc protection [(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine, be pearl foam solid (19.59 grams, 100% yield). ¹HNMR(DMSO-d ₆，400MHz)δ8.18(d，1H)，7.83(d，1H)，7.59(dd，1H)，7.48(t，1H)，6.25(q，1H)，1.75(d，3H)，1.39(s，9H)，1.19(s，9H)。

In the 5-bromo-3-of two-boc protection [(R)-1-(2; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine (19.58 grams; 33.76 mmole) in the solution in DMSO (68 milliliters); Add potassium acetate (11.26 grams, 114.78 mmoles) and two (any acyl (pinacolato) base frequently) two boron (10.29 grams, 40.51 mmoles).Make the mixture degassing, and load nitrogen three times, add Pd (dppf) Cl then ₂.CH ₂Cl ₂(1.38 grams, 1.69 mmoles).Make the reaction mixture degassing, and load nitrogen three times, then under 80 ℃ of oil baths, under nitrogen, stirred 12 hours.Make reaction cooled to envrionment temperature, with ETHYLE ACETATE (100 milliliters) dilution, and through the Celite pad filtration with the ETHYLE ACETATE washing.The ethyl acetate solution (700 milliliters) that merges is washed with water (5x100 milliliter), salt solution (100 milliliters), and with Na ₂SO ₄Dry.After filtering and concentrating, make residue purifying on silicagel column, with EtOAc/ hexane (0%-50%) wash-out; With 3-that two-boc protection is provided [(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-and pyridine-2-base amine, be foam solid (20.59 grams, 97% yield). ¹HNMR(DMSO-d ₆，400MHz)δ8.20(d，1H)，7.70(d，1H)，7.63(dd，1H)，7.47(t，1H)，6.20(q，1H)，1.73(d，3H)，1.50-1.13(m，30H)。

In the 3-of two-boc protection [(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine (20.34 restrain 32.42 mmoles) at CH ₂Cl ₂In the solution in (80 milliliters), add anhydrous HCl two

Solution in the alkane (4N, 40.5 milliliters, 162 mmoles).Reaction soln under 40 ℃ of oil baths, was stirred 12 hours under nitrogen.Make reaction mixture be cooled to envrionment temperature, with EtOAc (400 milliliters) dilution, then carefully but apace with saturated NaHCO ₃Washing is an alkalescence (pH＞8) up to water layer.With organic layer with brine wash, and with Na ₂SO ₄Dry.After filtration, evaporation and high vacuum dry, acquisition 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-and pyridine-2-base amine, be pearl foam solid (13.48 grams, 97% yield). ¹HNMR(DMSO-d ₆，400MHz)δ8.01(d，1H)，7.27(dd，1H)，7.17(d，1H)，7.03(t，1H)，6.12(q，1H)，5.08(bs，2H)，1.81(d，3H)，1.30(s，6H)，1.28(s，6H)。

In 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine (4.2711 grams; 10.0 mmole) with 4-(4-bromo-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester (consulting program 11) (3.9628 gram, 12.0 mmoles) in DME (40 milliliters) in stirred solution, add Na ₂CO ₃(3.1787 grams, 30.0 mmoles) solution in water (10 milliliters).Make the solution degassing, and load nitrogen three times.In this solution, add Pd (PPh ₃) ₂Cl ₂(351 milligrams, 0.50 mmole).Make the reaction soln degassing, and the nitrogen three times of recharging.Reaction soln in stir about under 87 ℃ of oil baths 16 hours (or till the borine pinacol ester consumes), is cooled to envrionment temperature, and dilutes with EtOAc (200 milliliters).Reaction mixture is filtered through Celite pad, and wash with EtOAc.With EtOAc solution with brine wash, with Na ₂SO ₄Drying, and concentrate.Make crude product purifying on silicagel column; With EtOAc/ hexane system (0%EtOAc to 100%EtOAc) wash-out; And 4-(4-{6-amino-5-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester (3.4167 grams, 65% yield;～95% purity), having Rf is 0.15 (50%EtOAc/ hexane).MS?m/e?550(M+1) ⁺。

In 4-(4-{6-amino-5-[(R)-1-(2; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-(566.7 milligrams of piperidines-1-carboxylic acid uncle-butyl ester; 1.03 mmole) in the solution in methyl alcohol (5 milliliters) or methylene dichloride (30 milliliters), interpolation 4N HCl/ two alkane (15 milliliters).With about 1 hour of solution stirring, or up to removing till protection accomplishes.Evaporating solvent, and residue is dissolved in the methyl alcohol, and on anti-phase C-18 preparation HPLC purifying, having the acetonitrile/water of 0.1% acetate, from 5% to 30%, with linear gradient elution.After freeze-drying, acquisition 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyridine-2-base amine acetate, be white solid (410 milligrams, 78% yield, 100%HPLC purity, 96.4% enantiomeric excess). ¹HNMR(DMSO-d ₆，400MHz)δ7.84(s，1H)，7.68(d，1H)，7.50(dd，1H)，7.46(s，1H)，7.37(t，1H)，6.83(d，1H)，6.02(q，1H)，5.57(bs，2H)，4.09(m，1H)，2.98(m，2H)，2.53(m，2H)，1.88(m，2H)，1.82(s，3H)，1.73(d，3H)，1.70(m，2H)。MS?m/e?450(M+1) ⁺。

General procedure 7:

Be that 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyridine-2-base amine (program 6) (150 milligrams, 0.288 mmole) of HCl salt is in CH ₂Cl ₂In the suspension-s in (2 milliliters), add NEt ₃(0.121 milliliter, 0.863 mmole), and at room temperature stirred 30 minutes.Make reaction cooled to 0 ℃, and add the chloroformyl methyl esters of acetate, and at room temperature stirred 1 hour.To react monitoring, and after changing into desired product fully, add water (2 milliliters) through LC-MS.To react extraction, with Na with EtOAc (4x10 milliliter) ₂SO ₄Drying, and concentrate, and acetate 2-[4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-yl]-2-oxo-ethyl ester (164 milligrams, quantitative) of quantitative yield.

[([1-(2 for 4-{6-amino-5-for 4-in acetate 2-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-yl]-(164 milligrams of 2-oxo-ethyl esters; 0.298 mmole) in the solution in MeOH (4 milliliters); Add and be dissolved in the LiOH (7 milligrams, 0.298 mmole) in 1 ml water.To react and at room temperature stir 30 minutes, wherein LC-MS shows and to change into 1-[4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-yl]-2-hydroxyl-ethyl ketone fully.Make product purifying on anti-phase C-18 preparation HPLC, to have the acetonitrile/water of 0.1% acetate, from 10% to 40% wash-out.

General procedure 8:

Make 100 ml flasks dry in baking oven, and in dry nitrogen atmosphere, cool off with stirring rod.Flask is loaded onto rubber injection device cover cap.Under nitrogen, flask is immersed in the ice-water bath, and introduces 1.6 milliliters of 1.0M borine solution among (1.6 mmole) THF.Then, introduce 2-among the anhydrous THF (1.0 milliliters) (4-{5-amino-6-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-yl }-pyrazol-1-yl)-2-methyl-propionic acid (program 5) (0.1 gram, 0.221 mmole).Formed mixture was stirred 5 hours down in envrionment temperature and nitrogen, and slowly add 6NHCl (1.1 milliliters), then introduce H ₂O (1.1 milliliters) and MeOH (7.4 milliliters).With reaction mixture stirred overnight continuously.Evaporate most of solvent in a vacuum, use 1NNaOH solution then with adjustment pH to 11.Add water, and solution is extracted with EtOAc (3x30 milliliter), and with Na ₂SO ₄Dry.After filtering and concentrating, make crude product with anti-phase preparation HPLC purifying, to contain the acetonitrile/water of 0.1% acetate, from 10% to 60% wash-out.After pure level is divided freeze-drying, acquisition 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-2-methyl-third-1-alcohol acetate, be white solid (21 milligrams, 22% yield).

General procedure 9

In the ice-cold solution of substituted benzylalcohol (1.0 molar equivalent) and anhydrous tetrahydro furan (0.14M), under nitrogen atmosphere, add sodium hydride (1.0 molar equivalent) at leisure.After stirring 30 minutes, with speed dropwise fast,, add 3 in the THF through adding the liquid funnel, 5-two bromo-pyrazines-2-base amine (1.0 molar equivalent) is (0.56M).In case when add accomplishing, remove ice bath, and make and react on refluxed under nitrogen, and through the reversed-phase HPLC monitoring.After 18 hours, show most of initially 3 on the HPLC typical case, 5-two bromo-pyrazines-2-base amine is consumed, and makes reaction cooled to room temperature.Reaction mixture is concentrated, with the ETHYLE ACETATE dilution, and with brine wash.Make organic layer with anhydrous magnesium sulfate drying, and concentrate in a vacuum.Crude product is used silica gel purification,, and produce 5-bromo-3-(substituted-benzyloxy)-pyrazine-2-base amine, be white solid, the 60-90% yield with 1: 1 ethyl acetate/dichloromethane wash-out.

General procedure 10

Make 5-bromo-3-(substituted benzyloxy)-pyridine-2-base amine or 5-bromo-3-(substituted benzyloxy)-pyrazine-2-base amine (1 molar equivalent), substituted 4-pyrazolyl dihydroxyl borine or ester (1.2 molar equivalent), two (triphenyl phosphine) Palladous chloride II (0.03 molar equivalent) and yellow soda ash (3.0 molar equivalent) in ethylene glycol dimethyl ether and water (4: 1; 0.2M) in the mixture degassing; And load nitrogen three times, under nitrogen, being heated to then refluxes spends the night.Make reaction cooled to envrionment temperature, and dilute with ETHYLE ACETATE.With mixture with water, brine wash, with Na ₂SO ₄Drying, and on silicagel column purifying, and 5-(substituted pyrazole-4-yl)-3-(substituted benzyloxy)-pyridine-2-base amine or the basic amine of 5-(substituted pyrazole-4-yl)-3-(substituted benzyloxy)-pyrazine-2-.

General procedure 11:

In 4-hydroxy-piperdine-1-carboxylic acid uncle-butyl ester (7.94 gram, 39.45 mmoles) at CH ₂Cl ₂In (100 milliliters), be cooled to 0 ℃ in stirred solution, slowly add NEt ₃(5.54 milliliters, 39.45 mmoles) then add methane sulfonyl chloride (3.06 milliliters, 39.45 mmoles) and DMAP (48 milligrams, 0.39 mmole).With mixture stirred overnight under room temperature.In mixture, add water (30 milliliters).With CH ₂Cl ₂(3x30 milliliter) extraction, then dry (Na ₂SO ₄), and remove in a vacuum and desolvate, obtain 4-methanesulfonyloxy group-piperidines-1-carboxylic acid uncle-butyl ester, be white solid (11.00 grams,＞99% yield). ¹HNMR(CDCl ₃，400MHz)δ4.89(m，1H)，3.69(m，2H)，3.31(m，2H)，3.04(s，3H)，1.95(m，2H)，1.83(m，2H)，1.46(s，9H)。

In 4-bromo-pyrazoles (10.44 gram, 71.03 mmoles) in dry DMF (96 milliliters), be cooled to 0 ℃ in stirred solution, slowly add NaH (60%, in Dormant oils) (3.13 grams, 78.133 mmoles).Solution was stirred 1 hour down at 0 ℃.Slowly add 4-methanesulfonyloxy group-piperidines-1-carboxylic acid uncle-butyl ester (19.82 gram, 71.03 mmoles), and reaction is heated to 100 ℃ spends the night, or till learning that through NMR pyrazoles consumes.Make reaction cooled to room temperature, and add water (20 milliliters), then extract with EtOAc.The extract that merges is washed with the saturated NaCl aqueous solution (4x20 milliliter), with Na ₂SO ₄Drying, and concentrate, and get 4-(4-bromo-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester, be orange oil.This oil is used the silica gel chromatography purifying,,,, have R for white solid (10.55 grams, 45% yield) so that 4-(4-bromo-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester to be provided with 10%EtOAc/ hexane to 25%EtOAc/ hexane wash-out _f=0.4 (the 25%EtOAc/ hexane uses iodine as tinting material). ¹HNMR(CDCl ₃，400MHz)δ7.46(s，1H)，7.43(s，1H)，4.23(m，3H)，2.88(m，2H)，2.10(m，2H)，1.88(m，2H)，1.47(s，9H)。

In 4-(4-bromo-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester (500 milligrams, 1.515 mmoles) at CH ₂Cl ₂In the solution in (3 milliliters), add TFA (3 milliliters).To react at room temperature and stir, till LCMS shows that reaction is accomplished.Remove in a vacuum and desolvate, and residue is dissolved among the MeOH (15 milliliters).With the oxyhydroxide resin pH value of solution is adjusted to 9, and 4-(4-bromo-pyrazol-1-yl)-piperidines.

In 4-(4-bromo-the pyrazol-1-yl)-solution of piperidines (375 milligrams, 1.63 mmoles) in DMF (3.26 milliliters), add NEt ₃(230 microlitres, 1.63 mmoles), and stirred 5 minutes.Add methyl iodide (MeI) (1.63 milliliters, the 1MMeI among the DMF just processes), and will react stirred overnight at room temperature.Add water, and solution is extracted with EtOAc (4x10 milliliter).With organic solution with brine wash, with Na ₂SO ₄Drying concentrates, and dried in vacuum, and gets 4-(4-bromo-pyrazol-1-yl)-1-methyl-piperidines (251 milligrams, 63% yield).

General procedure 12:

In 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1H-pyrazoles-4-yl)-pyrazine-solution of 2-base amine (295 milligrams, 0.80 mmole) in dry DMF (4 milliliters), add NaH (60%, in Dormant oils, 30.7 milligrams, 0.80 mmole).Mixture was stirred 0.5 hour down in envrionment temperature and nitrogen, introduce 4-methanesulfonyloxy group-piperidines-1-carboxylic acid uncle-butyl ester (223.5 milligrams, 0.80 mmole) then.Reaction mixture under nitrogen, is heated to 90 ℃ in oil bath, goes through 0.5 hour, and be cooled to envrionment temperature.Water slowly is added in the mixture, it is extracted with EtOAc, with brine wash, and with Na ₂SO ₄Dry.Make crude product purifying on silicagel column,, be white solid (265 milligrams, 59% yield) so that 4-(4-{5-amino-6-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-yl }-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester to be provided.

In 4-(4-{5-amino-6-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-yl }-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester (265 milligrams, 0.48 mmole) at CH ₂Cl ₂In solution in, add 4NHCl/ two

Alkane (4 milliliters).Mixture was stirred under envrionment temperature one hour.In the evaporation after, residue is dissolved in the methyl alcohol (2.5 milliliters), and on anti-phase C-18 preparation HPLC purifying, to contain the acetonitrile/water of 0.1% acetate, with the linear gradient elution of 10%-40%.After freeze-drying, acquisition 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyrazine-2-base amine acetate, be white solid (125 milligrams, 51% yield).

General procedure 13:

With phosphorus pentafluoride O-(7-azepine benzo triazol-1-yl)-N; N; N '; (HATU) (66 milligrams of N '-tetramethyl-urea ; 0.17 mmole) be added into (0.024 milliliter of 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-propionic acid (69 milligrams, 0.16 mmole), triethylamine; 0.17 mmole) and in the solution of 3-dimethylamino-propylamine (0.022 milliliter, 0.17 mmole) in 1.6 milliliters of DMF.After stirring 3 hours, make reaction through rotary evaporation concentration.Make residue pass through the silica gel chromatography purifying; Use the gradient eluent of methylene dichloride, methyl alcohol, volatile caustic; ([1-(2 for 4-{6-amino-5-to obtain 2-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(3-dimethylamino-propyl group)-propionic acid amide (41 milligrams, 50%).

General procedure 14:

With compound 14-1(1.3 molar equivalent) is added in the solution of aryl halide (0.21 mmole) in 3 milliliters of DME.Mixture is purged for several times with nitrogen, add two (triphenylphosphinyl) palladiums (II) (0.05 molar equivalent) of dichloro then.With 0.6 milliliter of H ₂Yellow soda ash among the O (3 molar equivalent) is added in the reaction mixture, and formed solution is heated to 85 ℃, goes through 12 hours.Water is added in the reaction mixture, so that the reaction cancellation.Add EtOAc then, with extraction water solution.Make the EtOAc layer with Na ₂SO ₄Dry.Leach Na ₂SO ₄, and make the filtrating evaporation, and get the Vandyke brown oil residue.Make residue pass through the silica gel chromatography purifying (with CH ₃OH, CH ₂Cl ₂, EtOAc and hexane wash-out), and desired product compound 14-2

General procedure 15:

The explanation of this general procedure (6-amino-3-aza-bicyclo also [3.1.0] oneself-the 3-yl)-([1-(2 for 4-{6-amino-5-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-phenyl)-specific embodiments of ketone, but can make amendment to form other compound through selection aryl halide or the heteroaryl halogen ArX that is fit to.

In [3-(4-iodo-benzoyl-)-3-aza-bicyclo also [3.1.0] oneself-6-yl]-carboxylamine uncle-butyl ester (100 milligrams, 0.234 mmole) and 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4; 4,5,5-tetramethyl--[1; 3; 2] dioxane pentaborane-2-yl)-mixture of pyridine-2-base amine (100 milligrams, 0.234 mmole) in DME (2 milliliters) in, add Pd (dppf) ₂Cl ₂.CH ₂Cl ₂(10 milligrams, 0.012 mmole) and Cs ₂CO ₃(351 milligrams, 0.702 mmole).Mixture was bubbled 10 minutes, then in 150 ℃ of following microwaves 30 minutes with nitrogen.LCMS affirmation reaction is accomplished.Crude reaction mixture is diluted with ETHYLE ACETATE, then with water and brine wash.With solution with MgSO ₄Dry.Through the preparation HPLC purifying, obtain solid.Solid was at room temperature stirred 3 hours with 4N HCl/ two alkane (3 milliliters).Remove volatile matter; Cause residue, make its purifying through preparation HPLC, and get (6-amino-3-aza-bicyclo also [3.1.0] oneself-the 3-yl)-([1-(2 for 4-{6-amino-5-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-phenyl)-ketone (30 milligrams, yield 26%).

General procedure 16:

Diethylazodicarboxylate's (0.48 milliliter, 3.1 mmoles) is added in 0 ℃ of solution of triphenylphosphine (0.80 gram, 3.1 mmoles) in THF (20 milliliters).After stirring 5 minutes, add 4-bromo-pyrazoles (0.30 milligram, 2.0 mmoles).Behind the restir 5 minutes, add (2-hydroxyethyl)-methyl-carboxylamine uncle-butyl ester (0.45 gram, 2.6 mmoles).Make reaction be warmed to room temperature and stirred overnight.Make reaction cooled to 0 ℃, and filter.Through rotary evaporation, make filtrating concentrating.Make residue pass through the silica gel chromatography purifying, use the gradient elution of methylene dichloride, ETHYLE ACETATE, obtain [2-(4-bromo-pyrazol-1-yl)-ethyl]-methyl-carboxylamine uncle-butyl ester (541 milligrams, 87%).

General procedure 17:

Sodium hydride (0.12 gram, 4.9 mmoles) is added in the solution of 4-bromo-4H-pyrazoles (0.60 gram, 4.1 mmoles) in DMF (10 milliliters).After stirring 10 minutes, add the solution (4 milliliter) of 2-chloro-methyl propionate in DMF.After stirring 4 hours, make to be reflected between ETHYLE ACETATE and the water and distribute.Separate phase, and with water with ethyl acetate extraction.The organic phase that makes merging is with MgSO ₄Drying, and through rotary evaporation concentration.Make residue pass through the silica gel chromatography purifying, use ETHYLE ACETATE and hexane gradient elutriant, and get 2-(4-bromo-pyrazol-1-yl)-methyl propionate (733 milligrams, 77%).

General procedure 18:

With (34 milligrams of LiOH; 1.4 the solution in water (0.4 milliliter) mmole); ([1-(2 for 4-{6-amino-5-to be added into 2-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl-pyrazol-1-yl)-solution of methyl propionate (70 milligrams, 0.15 mmole) in the mixture of THF (1.5 milliliters) and MeOH (0.4 milliliter) in.After stirred overnight, make to react between methylene dichloride and the half saturated brine and distribute.Add small amount of ethanol, and the pH value is adjusted to 7 with 1M HCl.Separate phase, and with water with dichloromethane extraction.The organic phase that makes merging is with Na ₂SO ₄Drying is filtered and through rotary evaporation concentration, and must 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-propionic acid (69 milligrams, 100%).

General procedure 19:

In 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-iodo-pyridine-2-base amine (100 milligrams, 0.23 mmole) and 3-methyl isophthalic acid H-pyrazoles (59 milligrams, 0.70 mmole) in DMSO (1 milliliter) in stirred solution, add K ₃PO ₄(101 milligrams, 0.47 mmole), dodecyl (0.015 milliliter, 0.05 mmole), cyclohexane diamine (0.009 milliliter, 0.07 mmole) and cupric iodide (CuI) (14 milligrams, 0.07 mmole).Solution was bubbled 5 minutes with nitrogen; Then under 150 ℃ with microwave radiation 2 hours; LCMS affirmation reaction is accomplished, makes mixture pass through the preparation HPLC purifying, and [1-(2 to stay 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(3-methyl-pyrazol-1-yl)-pyridine-2-base amine (30 milligrams), yield 34.2%.

General procedure 20:

In 4-(3-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-tetramethyleneimine-2-carboxylate methyl ester (105 milligrams, 0.21 mmole) in THF (5 milliliters) in stirred solution, add the 2M CH among the THF ₃NH ₂(1.06 milliliters, 2.12 mmoles) stir mixture; And under 55 ℃, heated 18 hours, LCMS affirmation reaction has been accomplished, removes THF; Make residue pass through the preparation HPLC purifying; Stay 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-tetramethyleneimine-2-carboxylic acid methyl acid amides (30 milligrams), yield 28.6%.

General procedure 21:

4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles-1-carboxylic acid uncle-butyl ester ( 21-1): two carbonic acid di-tert-butyls (7.2 molar equivalent), 4-(dimethylamino) pyridine (0.84 molar equivalent) are added into 4,4,5, and 5-tetramethyl--2-(1H-pyrazoles-4-yl)-1,3 is in the solution of 2-dioxane pentaborane (6 mmole) in 40 milliliters of DMF.Reaction mixture was at room temperature stirred 12 hours.Water is added in the reaction mixture, so that the reaction cancellation.Add EtOAc then, with extraction water solution.Make the EtOAc layer with Na ₂SO ₄Dry.Leach Na ₂SO ₄, and evaporated filtrate, and get isabelline oil residue, be compound 21-1(1.32 grams; 4.56 mmole; 76%). ¹HNMR (400MHz, the δ ppm1.32 of chloroform-D) (s, 12H) 1.63 (s, 9H) 7.91 (s, and 1H) 8.37 (s, 1H).Residue is used in the next step reaction, is not further purified.

Compound 21-3, with 3-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group]-5-(1H-pyrazoles-4-yl) pyridine-2-amine ( 21-3a) specific embodiments show:

With compound 21-1(1.0 molar equivalent) is added into compound 21-2a(compound 21-2, have the R substituting group, and 2,6-two chloro-3-fluoro-phenyl) in (1.92 mmole) solution in 20 milliliters of DME.Mixture was stirred 30 minutes under room temperature and nitrogen atmosphere, add two (triphenylphosphinyl) palladiums (II) (0.05 molar equivalent) of dichloro then.With 4 milliliters of H ₂Yellow soda ash among the O (3 molar equivalent) is added in the reaction mixture, and formed solution is heated to 85 ℃, goes through 12 hours.Employed alternate base is CsF and Cs ₂CO ₃, in 1 or 2 equivalent dihydroxyl borine esters, and at room temperature (CsF) or 80 ℃ (all).Water is added in the reaction mixture, so that the reaction cancellation.Then add EtOAc (150 milliliters of x2), with extraction water solution.Make the EtOAc layer with Na ₂SO ₄Dry.Leach Na ₂SO ₄, and evaporated filtrate, and get the Vandyke brown oil residue.Make residue pass through silica gel chromatography (with the 0 → 10%MeOH wash-out in the ETHYLE ACETATE) purifying, and get desired product compound 21-3a(2.05 grams, 53.6% yield). ¹HNMR (400MHz, δ ppm 1.60 (s, 1H) 1.84 (d, J=6.57Hz, 3H) 5.07 (s of chloroform-D); 2H) 6.06 (q, J=6.57Hz, 1H) 6.89 (d, J=1.77Hz, 1H) 6.96-7.06 (m; 1H) 7.22-7.33 (m, 1H) 7.67 (s, 2H) 7.80 (d, J=1.52Hz, 1H).

Can use following program of giving an example, to make formula 21-4 compound: sodium hydride (1.2 molar equivalent) is added into compound 21-3In (0.87 mmole) solution in 10 milliliters of DMF.Mixture was stirred 30 minutes under room temperature and nitrogen atmosphere, add compound then 21-6(1 molar equivalent).Formed solution is heated to 85-90 ℃, went through 12 hours.Water (20 milliliters) is added in the reaction mixture, so that the reaction cancellation.Then add EtOAc (50 milliliters of x2), with extraction water solution.Make the EtOAc layer with Na ₂SO ₄Dry.Leach Na ₂SO ₄, and make the filtrating evaporation.Make residue pass through silica gel chromatography (with the EtOAc wash-out in the hexane) purifying, and get desired product compound 21-4(20-50% yield).

General procedure 22:

L=Br, Cl, COOH, COCl, OMs, ethylene carbonate, aldehyde

Formula 22-3Compound can be processed through following program of giving an example: with compound 22-2(1.2 molar equivalent) is added into compound 22-1In (0.24 mmole) and alkali (3-5 molar equivalent) and/or the solution of coupling reagent (1 molar equivalent) in 5 milliliters of DMF.Mixture was stirred 12 hours under nitrogen atmosphere.Water (20 milliliters) is added in the reaction mixture, so that the reaction cancellation.Then, add EtOAc (50 milliliters of x2), with extraction water solution.Make the EtOAc layer with Na ₂SO ₄Dry.Leach Na ₂SO ₄, and make the filtrating evaporation.Make residue pass through silica gel chromatography (with CH ₃OH, CH ₂Cl ₂, EtOAc and hexane wash-out) purifying, and desired product compound 22-3

General procedure 23:

Following program can be in order to preparation piperidines-pyrazoles-2-aminopyrazole derivatives.

4-(4-iodo-1H-pyrazol-1-yl) piperidines-1-carboxylic acid uncle-butyl ester (23-1a)

Under 4 ℃, with NaH (1.2 equivalents, 0.68 mmole) gradation be added into 4-iodine pyrazoles (0.57 mmole) at DMF (2 liters) in stirred solution.Formed mixture was stirred 1 hour down in 4 ℃, and then add compound 23-4(1.1 equivalents, 0.63 mmole).With formed mixture heating up to 100 ℃, went through 12 hours.With H ₂O makes the reaction cancellation, and with the EtOAc extracted several times.Make the organic layer of merging dry, filter, and concentrate, and get orange oil.Make residue pass through silica gel chromatography (with the 5%EtOAc wash-out in the pentane) purifying, and get compound 23-1a, be white solid (140 grams, 66%).

4-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl] piperazine Pyridine-1-carboxylic acid uncle-butyl ester (23-1b)

Two (which acyl group frequently) two boron (1.4 equivalents, 134 grams, 0.52 mole) one after the other are added into compound with potassium acetate (4 equivalents, 145 grams, 1.48 moles) 23-1aIn (140 grams, 0.37 mole) solution in 1.5 liters of DMSO.Mixture is purged for several times with nitrogen, and then add two (triphenylphosphinyl) palladiums (II) of dichloro (0.05 equivalent, 12.9 grams, 0.018 mole).Formed mixture was heated 2 hours down at 80 ℃.Make reaction mixture be cooled to room temperature, and filter, and wash with EtOAc through bed of diatomaceous earth.To filtrate with saturated NaCl (500 milliliters of x2) washing, with Na ₂SO ₄Drying is filtered, and concentrates.Make residue pass through silica gel chromatography (with the 5%EtOAc wash-out in the hexane) purifying, and get compound 23-1b, be white solid (55 grams, 40%).

With compound 23-2(1.0 molar equivalent) is added into compound 23-1bIn (1.3 molar equivalent) solution in 15 milliliters of DME.Mixture is purged for several times with nitrogen, add two (triphenylphosphinyl) palladiums (II) (0.05 molar equivalent) of dichloro then.With 4 milliliters of H ₂Cesium carbonate among the O (3 molar equivalent) is added in the reaction mixture, and formed solution is heated to 85 ℃, goes through 12 hours.Water (10 milliliters) is added in the reaction mixture, so that the reaction cancellation.Then add EtOAc (150 milliliters of x2), with extraction water solution.Make the EtOAc layer with Na ₂SO ₄Dry.Leach Na ₂SO ₄, and evaporated filtrate, and get the Vandyke brown oil residue.Make residue pass through silica gel chromatography (with the 75 → 100%EtOAc wash-out in the hexane) purifying, and get compound 23-3a(61% yield).

Hydrochloride (19 equivalents, 12 mmoles) is added into compound 23-3aIn (0.63 mmole) solution in MeOH (4 milliliters).Mixture was stirred under room temperature 12 hours.Evaporating solvent, and add H ₂O (10 milliliters).Add saturated NaHCO ₃(aqueous solution), with neutralization solution to pH7.Add ETHYLE ACETATE (100 milliliters of x2), with extraction water solution.The organic layer that makes merging is with Na ₂SO ₄Drying is filtered, and evaporation, and gets compound 23-5a, be solid residue (0.6 mmole, 95% yield).

Formula 23-7Compound can form according to following general procedure: with compound 23-8(1.2 molar equivalent) is added into compound 23-5aIn (0.24 mmole) and alkali (3-5 molar equivalent) and/or the solution of coupling reagent (1 molar equivalent) in 5 milliliters of DMF.Mixture was stirred 12 hours under nitrogen atmosphere.Water (20 milliliters) is added in the reaction mixture, so that the reaction cancellation.Add EtOAc (50 milliliters of x2) then, with extraction water solution.Make the EtOAc layer with Na ₂SO ₄Dry.Leach Na ₂SO ₄, and evaporated filtrate, and get the oily residue.Make residue pass through silica gel chromatography (with CH ₃OH, CH ₂Cl ₂, EtOAc and hexane wash-out) purifying, and desired product compound 23-7a

General procedure 24:

3-methoxylation compound can pass through following general procedure, and system is from its corresponding 3-fluorine cpd.In 4 milliliters of DMSO, add 0.124 milliliter of ethanol, then add 32 milligrams of NaH.After stirring 30 minutes, add 250 milligrams 24-1, and reaction is heated to 40 ℃.After three hours, make reaction cooled, and pour in the water with deposition.After being neutralized to pH6, separated product 24-2.

General procedure 25:

In 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2,2-dimethyl--[1,3] dioxolane-4-ylmethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine (150 milligrams, 0.31 mmole) at THF (3 milliliters) and H ₂Among the O (2 milliliters) in stirred solution, under 0 ℃, add TFA (2 milliliters), mixture is stirred; And be warmed to room temperature, and to heat 5 hours down at 50 ℃ then, LCMS affirmation reaction has been accomplished; Remove THF, make residue pass through the preparation HPLC purifying, ([1-(2 for 4-{6-amino-5-to stay 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-propane-1,2-glycol (102 milligrams), yield 74.2%.

General procedure 26:

In 4-bromo-1H-pyrazoles in DMF in stirred solution, at room temperature, add sodium hydride.Mixture was stirred 30 minutes, add [1,3] dioxolane-2-ketone, mixture is stirred, and be warmed to room temperature at leisure.Through the TLC monitoring reaction.After reaction has been accomplished, add EtOAc, with saturated NaHCO ₃, water and brine wash, with Na ₂SO ₄Drying is filtered, and concentrates.Make residue pass through silica gel, eluent EtOAc and DCM10% purifying, and get 2-(4-bromo-pyrazol-1-yl)-ethanol 0.22 gram, yield 34%. ¹HNMR (400MHz, the δ ppm 7.49 of chloroform-D) (s, 1H) 7.46 (s, 1H) 4.18-4.23 (m, 2H) 3.93-3.98 (m, 2H) 3.09 (s, 1H).

General procedure 27

In dry round-bottomed flask, add pyrazoles (1 equivalent) and NaH (1 equivalent) in the dry DMF (0.2M).Add desired nucleophilic reagent (1 equivalent), and heat 17 hours under will reacting on 90 ℃.In reaction mixture, add water (20 milliliters) and EtOAc (20 milliliters).Water layer with EtOAc (4x20 milliliter) extraction, is followed dry (Na ₂SO ₄), and remove in a vacuum and desolvate, and get desired crude product.Through the silica gel column chromatography purifying.

General procedure 28

In 2,6-two chloro-3,5-two fluoro-phenol (25 grams, 125.62 mmoles) are at CH ₂Cl ₂In (250 milliliters), be cooled to 0 ℃ in stirred solution, slowly add N-methylmorpholine (21 milliliters, 188.43 mmoles), then add Trifluoromethanesulfonic anhydride (32 milliliters, 188.43 mmoles).With mixture stirred overnight under room temperature.In mixture, add water (50 milliliters).With CH ₂Cl ₂(3x50 milliliter) extraction, then dry (Na ₂SO ₄), and remove in a vacuum and desolvate, obtain 28-2, be oily matter (42.18 grams,＞99% yield). ¹HNMR(CDCl ₃，400MHz)δ7.15(t，1H)。

In three fluoro-methanesulfonics 2,6-two chloro-3,5-two fluoro-phenyl esters 28-2(42.18 gram, 127.43 mmoles) and 4,4,5,5-tetramethyl--2-vinyl-[1,3,2] dioxane pentaborane (21.59 grams, 140.17 mmoles) in DME (200 milliliters) in stirred solution, add the Na in water-soluble (50 milliliters) ₂CO ₃(40.52 grams, 382.29 mmoles).The solution that makes merging is with N ₂Degassing 3x.Add dichloro triphenyl phosphine palladium (1.78 grams, 2.54 mmoles), and make reaction soln with N ₂3x again outgases.To react on 70 ℃ stirred 15 hours down.Make reaction cooled to room temperature, and add EtOAc (50 milliliters).Solution is filtered through Celite pad, and with EtOAc and water washing.Water layer is extracted with EtOAc (3x milliliter).The organic substance that makes merging is with Na ₂SO ₄Drying, and remove in a vacuum and desolvate, obtain 28-3, be orange oil.Make this oil on silicagel pad, with 5%EtOAc/ hexane purifying, to obtain clean oil (26.12 grams, 99% yield). ¹HNMR(CDC1 ₃，400MHz)δ6.96(t，1H)，6.66(m，1H)，5.85(m，2H)。

Make 28-3(26.63 grams, 127.43 mmoles) are at CH ₂Cl ₂In (320 milliliters), through being cooled to-78 ℃ solution, with ozone (O ₃) bubbled 30 minutes, till reaction is transformed into mazarine.Then, will react with N ₂Purged 5 minutes.Slowly add dimethyl thioether (50 milliliters, 637.15 mmoles), make the reaction color yellowing.Make reaction be warmed to room temperature.Organic substance is washed with water (3x50 milliliter).Make organic substance with Na ₂SO ₄Drying, and remove in a vacuum and desolvate, obtain 28-4, be orange oil (17.13 grams, 65% yield). ¹HNMR(CDCl ₃，400MHz)δ10.43(s，1H)，7.24(t，1H)。

With N ₂In the dry round-bottomed flask that purges, add among the THF (109 milliliters) 28-4MeMgBr (64.3 milliliters, 90.04 mmoles, 1.4M is in THF) through being cooled to 0 ℃, is added at leisure in (17.13 gram, 81.85 mmoles).To react and at room temperature stir 15 hours.Add saturated NH ₄The Cl aqueous solution (30 milliliters) and EtOAc (30 milliliters) extract water layer then with EtOAc (3x30 milliliter).The organic substance that makes merging is with Na ₂SO ₄Drying, and remove in a vacuum and desolvate, obtain 28-5, be orange oil (16.9 grams, 92% yield). ¹HNMR(CDCl ₃，400MHz)δ6.98(t，1H)，5.62(m，1H)，1.65(d，3H)。

In 28-5(16.90 grams, 75.169 mmoles) are at CH ₂Cl ₂In (150 milliliters), be cooled to 0 ℃ in stirred solution, slowly add NEt ₃(10.7 milliliters, 75.169 mmoles) then add methane sulfonyl chloride (5.94 milliliters, 75.169 mmoles) and DMAP (92 milligrams, 0.075 mmole).With mixture stirred overnight under room temperature.In mixture, add water (50 milliliters).With CH ₂Cl ₂(3x50 milliliter) extraction, then dry (Na ₂SO ₄), and remove in a vacuum and desolvate, obtain 28-6 (21.48 grams, 95% yield). ¹HNMR(CDCl ₃，400MHz)δ7.07(t，1H)，6.48(m，1H)，2.96(s，3H)。

In 28-6(1.15 gram, 3.78 mmoles) and 2-amino-5-bromo-pyridine-3-alcohol (3.78 grams, 3.78 mmoles) DMF (8 milliliters, in 0.5M) in stirred solution, add Cs ₂CO ₃(1.23 grams, 3.78 mmoles).Reaction mixture was stirred 17 hours down in 60 ℃.Make reaction cooled to room temperature, and add water (20 milliliters).Solution is extracted with EtOAc (4x20 milliliter), with Na ₂SO ₄Drying, and remove in a vacuum and desolvate.Make rough reaction through the silica gel column chromatography purifying, and get faint yellow solid 28-7(600 milligrams, 41% yield). ¹HNMR(CDCl ₃，400MHz)δ7.69(s，1H)，7.04(t，7.04)，6.01(m，1H)，4.80(bs，2H)，1.82(d，3H)。

In 28-7(395 milligrams, 1 mmole) and dioxane pentaborane (565 milligrams, 1.5 mmoles) in DME (200 milliliters) in stirred solution, add the Cs in water-soluble (1 milliliter) ₂CO ₃(975 milligrams, 3 mmoles).The solution that makes merging is with N ₂Degassing 3x.Add Pd (dppf) ₂CH ₂Cl ₂(41 grams, 0.05 mmole), and make reaction soln with N ₂3x again outgases.To react on 70 ℃ stirred 15 hours down.Make reaction cooled to room temperature, and add EtOAc (25 milliliters).Solution is filtered through Celite pad, and with EtOAc and water washing.Water layer is extracted with EtOAc (3x25 milliliter).The organic substance that makes merging is with Na ₂SO ₄Drying, and remove in a vacuum and desolvate, obtain 28-8, be brown solid.Make crude product pass through silica gel chromatography purifying (436 milligrams, 77% yield).Make the BOC product be dissolved in CH ₂Cl ₂In (5 milliliters), and add 4M HCl/ two

Alkane (2 milliliters).To react and stir 1 hour, till LCMS shows removal protection fully.Add water (10 milliliters), and separation of C H ₂Cl ₂Layer.Organic substance is washed with water (3x10 milliliter).The water layer that makes merging is with Na ₂CO ₃Be neutralized to pH7, and with CH ₂Cl ₂(4x10 milliliter) extraction is with Na ₂SO ₄Drying, and in a vacuum except that desolvating (quantitative yield). ¹HNMR(400MHz，DMSO)δ7.92(s，1H)，7.81(m，1H)，7.76(s，1H)，7.53(s，1H)，6.90(s，1H)，6.12(m，1H)，5.65(bs，2H)，4.12(m，1H)，3.00(m，2H)，2.66(m，2H)，1.90(m，2H)1.80(d，3H)，1.70(m，2H)。

General procedure 29

In the microwave container that oven drying is crossed, add nucleophilic reagent (OH, alkoxyl group or amine) (0.2 mmole) and alkali (NaH, 0.2 mmole) in the dry DMF.Reaction vessel is added a cover, and in microwave, heated 30 minutes down at 120 ℃.After replacing fully, in reaction mixture, add water (20 milliliters) and EtOAc (20 milliliters).Water layer is extracted with EtOAc (4x20 milliliter).Merge organic substance, and with water (3x20 milliliter) washing, with Na ₂SO ₄Drying, and remove in a vacuum and desolvate.Through the HPLC purifying.In the compound (0.2 mmole) that contains BOC protection base, add CH ₂Cl ₂(5 milliliters), and add 4M HCl/ two

Alkane (2 milliliters).To react and stir 1 hour, till LCMS shows removal protection fully.Add water (10 milliliters), and separation of C H ₂Cl ₂Layer.Organic substance is washed with water (3x10 milliliter).The water layer that makes merging is with Na ₂CO ₃Be neutralized to pH7, and with CH ₂Cl ₂(4x10 milliliter) extraction is with Na ₂SO ₄Drying, and remove in a vacuum and desolvate.Through the HPLC purifying.

Embodiment 1: 3-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl] azetidine-1-carboxylic acid uncle-butyl ester

Title compound is according to program 1 (compound 1-9) process. ¹H?NMR(400MHz，DMSO-D6)δppm?1.25-1.33(m，9H)1.69-1.77(m，3H)2.80-2.97(m，1H)3.60(s，2H)3.81(s，2H)4.22(d，J＝7.07Hz，2H)5.59(s，2H)6.01(q，J＝6.32Hz，1H)6.81(d，J＝1.26Hz，1H)7.37(t，J＝8.84Hz，1H)7.43-7.54(m，1H)7.55-7.62(m，1H)7.67(d，J＝1.52Hz，1H)7.84(s，1H)；LCMS：537[M+1]；c-MetKi：0.066μM。

Embodiment 2: 5-[1-(azetidine-3-ylmethyl)-1H-pyrazoles-4-yl]-3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridine-2-amine

Title compound is according to program 1 (compound 1-10) process. ¹HNMR(400MHz，MeOD)δppm?1.78(d，J＝6.57Hz，3H)3.32(d，J＝8.08Hz，1H)3.84-3.95(m，2H)4.00(t，J＝9.73Hz，2H)4.29(d，J＝6.82Hz，2H)6.08(d，J＝6.57Hz，1H)6.83(s，1H)7.14(t，J＝8.59Hz，1H)7.35(dd，J＝8.84，4.80Hz，1H)7.48(s，1H)7.57(s，1H)7.69(s，1H)；LCMS：437[M+1]；c-MetKi：0.044μM。

Embodiment 3: 4-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl]-4-hydroxy piperidine-1-carboxylic acid uncle-butyl ester

Title compound is according to program 3 (compounds 3-6) process. ¹HNMR(400MHz，DMSO-D6)δppm1.34-1.39(m，9H)1.70-1.77(m，2H)1.79(d，J＝6.57Hz，3H)3.06(d，J＝12.63Hz，2H)3.62(s，2H)4.03(s，2H)4.79(s，1H)5.66(s，2H)6.08(d，J＝6.82Hz，1H)6.86(d，J＝1.52Hz，1H)7.44(t，J＝8.72Hz，1H)7.51-7.58(m，2H)7.58-7.65(m，2H)7.73(d，J＝1.52Hz，1H)7.78(s，1H)；LCMS：581[M+1]；c-MetKi：0.104μM。

Embodiment 4: 4-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl] piperidines-4-alcohol

Title compound is according to program 3 (compounds 3-7) process. ¹HNMR(400MHz，DMSO-D6)δppm1.41-1.55(m，2H)1.59-1.71(m，2H)1.81(d，J＝6.57Hz，3H)2.88-3.00(m，2H)3.02-3.14(m，2H)4.08(s，2H)5.17(s，2H)6.14-6.27(m，J＝6.57Hz，1H)7.05(s，1H)7.40-7.49(m，J＝8.72，8.72Hz，1H)7.51-7.60(m，J＝9.09，4.80Hz，1H)7.63(s，1H)7.76(s，1H)7.91(s，1H)8.51(s，1H)8.81(s，1H)；LCMS：481[M+1]；c-MetKi：0.062μM。

Embodiment 5: 5-(1-azetidine-3-base-1H-pyrazoles-4-yl)-3-[1-(2,6-two fluoro-3-fluorophenyls) oxyethyl group] pyridine-2-amine

Title compound is according to program 2 (compounds 2-11) process. ¹HNMR(400MHz，DMSO-D6)δppm?1.79-1.89(m，3H)3.56(s，1H)4.35(s，4H)5.40(s，1H)6.23(d，J＝6.57Hz，2H)7.09(s，1H)7.40-7.54(m，1H)7.59(dd，J＝8.84，5.05Hz，1H)7.73-7.83(m，1H)7.86(s，1H)8.12(s，1H)9.20(s，1H)；LCMS：523[M+1]；c-MetKi：0.033μM。

Embodiment 6: 5-{1-[1-(cyclopropyl methyl) azetidine-3-yl]-1H-pyrazoles-4-yl }-3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridine-2-amine

Title compound is processed according to program 2. ¹HNMR(400MHz，DMSO-D6)δppm0.12(s，2H)0.41(s，2H)0.76(s，1H)1.79(d，J＝6.57Hz，3H)2.27-2.40(m，J＝2.02Hz，2H)2.44(d，J＝1.77Hz，2H)3.74(s，2H)4.94(s，1H)5.66(s，2H)5.99-6.17(m，1H)6.89(s，1H)7.43(t，J＝8.72Hz，1H)7.52-7.65(m，2H)7.75(s，1H)8.02(s，1H)；LCMS：477[M+1]；c-MetKi：0.038μM。

Embodiment 7: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(1-{1-[(dimethylamino) ethanoyl] azetidine-3-yl }-1H-pyrazoles-4-yl) pyridine-2-amine

Title compound is processed according to program 2. ¹HNMR(400MHz，DMSO-D6)δppm1.78(d，J＝6.82Hz，3H)2.17(s，6H)2.89-2.98(m，2H)4.07-4.16(m，1H)4.30(t，J＝9.09Hz，1H)4.36-4.45(m，1H)4.60(t，J＝8.59Hz，1H)5.15-5.27(m，1H)5.64-5.73(m，2H)6.08(q，J＝6.48Hz，1H)6.90(s，1H)7.38-7.48(m，J＝8.72，8.72Hz，1H)7.50-7.61(m，J＝8.84，5.05Hz，1H)7.66(s，1H)7.71-7.79(m，1H)8.05(s，1H)；LCMS：508[M+1]；c-MetKi：0.022μM。

Embodiment 8: [3-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) azetidine-1-yl] acetonitrile

Title compound is processed according to program 2. ¹HNMR(400MHz，DMSO-D6)δppm?1.79(d，J＝6.82Hz，3H)3.59(q，J＝6.57Hz，2H)3.68-3.79(m，4H)5.00(t，J＝6.95Hz，1H)5.72(s，2H)6.03-6.13(m，J＝6.57Hz，1H)6.89(d，J＝1.52Hz，1H)7.43(t，J＝8.72Hz，1H)7.56(dd，J＝9.09，5.05Hz，1H)7.62(s，1H)7.74(d，J＝1.52Hz，1H)8.01(s，1H)；LCMS：462[M+1]；c-MetKi：0.025μM。

Embodiment 9: 2-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl] the cyclopropane carboxylic acid acetoacetic ester

Title compound is according to program 4 (compounds 4-6) process. ¹HNMR(400MHz，DMSO-D6)δppm0.96-1.10(m，2H)1.15(t，J＝7.07Hz，2H)1.74(s，3H)1.79(d，J＝6.57Hz，3H)3.95-4.14(m，4H)5.66(s，2H)6.08(d，J＝6.57Hz，1H)6.88(s，1H)7.43(t，J＝8.72Hz，1H)7.49-7.62(m，2H)7.73(s，1H)7.88(s，1H)；LCMS：494[M+1]；c-MetKi：0.042μM。

Embodiment 10: 2-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl]-N-methyl cyclopropane methane amide

Title compound is according to program 4 (compounds 4-8) process. ¹HNMR(400MHz，DMSO-D6)δppm0.72-0.82(m，1H)0.86-0.95(m，1H)1.18-1.32(m，1H)1.51-1.66(m，2H)1.82(d，J＝6.57Hz，3H)2.53-2.58(m，3H)3.98-4.10(m，2H)6.18(d，J＝6.32Hz，1H)7.09(s，1H)7.22(s，1H)7.34(s，1H)7.46(t，J＝8.59Hz，1H)7.54-7.63(m，1H)7.76(s，1H)7.97(s，1H)8.04(d，J＝4.55Hz，1H)；LCMS：479[M+1]；c-MetKi：0.071μM。

^{Embodiment 11}: 2-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl]-N, the N-dimethyl-cyclopropane carboxamide

Title compound in the end uses n n dimetylaniline to process according to program 4 in the step. ¹HNMR(400MHz，DMSO-D6)δppm0.78-0.90(m，1H)0.94-1.07(m，1H)1.56(s，1H)1.81-1.90(m，3H)1.97-2.11(m，1H)2.77(s，3H)3.02(d，J＝4.80Hz，3H)4.01-4.08(m，1H)4.08-4.22(m，1H)6.95(s，1H)7.04-7.14(m，2H)7.21(s，1H)7.48(t，J＝8.72Hz，1H)7.57-7.62(m，J＝9.22，4.93Hz，1H)7.64(d，J＝2.78Hz，1H)7.70(d，J＝1.26Hz，1H)7.98-8.08(m，1H)；LCMS：492[M+1]；c-MetKi：0.144μM。

Embodiment 12: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-2-methyl-propionic acid

Title compound is according to program 5 (compounds 5-2) process. ¹HNMR(400MHz，DMSO)δ8.10(S，1H)，7.83(S，1H)，7.60(m，3H)，7.46(m，1H)，6.98(m，1H)，6.15(m，1H)，1.84(d，2H)，1.75(s，6H)；LCMS：453[M+1]；c-MetKi：0.18μM。

Embodiment 13: 5-(5-amino-1-methyl isophthalic acid H-pyrazoles-4-yl)-3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine and 4-bromo-2-methyl-2H-pyrazole-3-yl amine to process according to program 6. ¹HNMR(400MHz，CDCl ₃)δ7.42(s，1H)，7.35(m，1H)，7.29(s，1H)，6.95(m，1H)，6.15(m，1H)，3.75(s，3H)，1.90(d，2H)；LCMS：396[M+1]；c-MetKi：0.13μM。

Embodiment 14: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(5-methyl isophthalic acid H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine and 4-bromo-5-methyl isophthalic acid H-pyrazoles to process according to program 6. ¹HNMR(400MHz，CDCl ₃)δ7.34(m，2H)，7.15(m，2H)，6.88(s，1H)，6.13(m，1H)，2.27(s，3H)，1.93(d，J8Hz，3H)；LCMS：380[M+1]；c-MetKi：0.70μM。

Embodiment 15: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(3,5-dimethyl--1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine and 4-bromo-3 according to program 6, and 5-dimethyl--1H-pyrazoles is processed. ¹HNMR(400MHz，CDCl ₃)δ7.35(m，1H)，7.20(s，1H)，7.14(m，1H)，6.7(s，1H)，6.10(m，1H)，2.13(s，6H)，1.92(d，J8Hz，3H)；LCMS：395[M+1]；c-MetKi：0.15μM。

Embodiment 16: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(3-dimethylamino-propyl group)-isobutyramide

Title compound is according to program 5 (compounds 5-3) process. ¹HNMR(400MHz，CDCl ₃)δ7.71(s，1H)，7.63(s，1H)，7.46(s，1H)，7.35(m，1H)，7.13(m，2H)，7.00(m，1H)，6.18(m，1H)，3.32(m，2H)，3.01(m，2H)，2.78(s，6H)，1.96(m，2H)，1.94(m，2H)，1.84(s，6H)；LCMS：537[M+1]；c-MetKi：0.06μM。

Embodiment 17: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-2-methyl isophthalic acid-piperazine-1-base-third-1-ketone

Title compound in the end uses piperazine-1-carboxylic acid uncle-butyl ester as amine according to program 5 in the step, then use the 20%TFA in the methylene dichloride, removes Boc-protection base and processes with ordinary method. ¹HNMR(400MHz，CDCl ₃)δ7.63(s，1H)，7.58(s，1H)，7.51(m，1H)，7.35(m，1H)，7.13(m，1H)，7.02(s，1H)，6.17(m，1H)，2.90(m，4H)，1.93(d，J8Hz，2H)，1.80(s，6H)；LCMS：521[M+1]；c-MetKi：0.44μM。

Embodiment 18: 2-(4-(6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl)-pyrazol-1-yl)-1-((R)-3-hydroxyl-tetramethyleneimine-1-yl)-2-methyl-third-1-ketone

Title compound in the end uses (R)-tetramethyleneimine-3-alcohol to process as amine according to program 5 in the step. ¹HNMR(400MHz，CDCl ₃)δ7.60(m，2H)，7.50(s，1H)，7.31(m，1H)，7.14(m，1H)，7.04(s，1H)，6.17(m，1H)，4.37(m，1H)，3.70(m，2H)，2.65(m，2H)，1.94(d，J8Hz，3H)，1.81(m，8H)；LCMS：522[M+1]；c-MetKi：0.27μM。

Embodiment 19: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(2-morpholine-4-base-ethyl)-isobutyramide

Title compound in the end uses (2-morpholine-4-base ethyl) amine to process as amine according to program 5 in the step. ¹HNMR(400MHz，CDCl ₃)δ7.69(m，2H)，7.58(s，1H)，7.47(s，1H)，7.34(m，1H)，7.13(m，1H)，7.08(s，1H)，6.18(m，1H)，3.95(m，4H)，3.65(m，2H)，3.50(m，2H)，3.19(m，2H)，2.90(m，2H)，1.94(d，J8Hz，3H)，1.83(s，6H)；LCMS：565[M+1]；c-MetKi：0.14μM。

Embodiment 20: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-sec.-propyl-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound uses 2-iodo-propane to process as alkylating reagent according to program 5. ¹HNMR(400MHz，CDCl ₃)δ7.53(s，1H)，7.48(s，1H)，7.43(s，1H)，7.35(m，1H)，7.13(m，1H)，7.02(s，1H)，6.15(m，1H)，4.50(m，1H)，1.93(d，J8Hz，3H)，1.52(d，J4Hz，6H)；LCMS：409[M+1]；c-MetKi：0.04μM。

Embodiment 21: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(2-tetramethyleneimine-1-base-ethyl)-isobutyramide

Title compound in the end uses (2-tetramethyleneimine-1-base ethyl) amine to process as amine according to program 5 in the step. ¹HNMR(400MHz，CDCl ₃)δ7.70(s，1H)，7.61(s，1H)，7.46(m，1H)，7.35(m，1H)，7.13(m，1H)，7.09(m，1H)，6.18(m，1H)，3.79(m，2H)，3.62(m，1H)，3.24(m，1H)，2.81(m，1H)，2.10(m，4H)，1.93(d，J8Hz，3H)，1.84(s，6H)；LCMS：549[M+1]；c-MetKi：0.06μM。

Embodiment 22: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-isobutyl--1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound uses 1-iodo-2-methyl-propane to process as alkylating reagent according to program 5. ¹HNMR(400MHz，CDCl ₃)δ7.52(m，1H)，7.48(m，1H)，7.40(m，1H)，7.35(m，1H)，7.11(m，1H)，7.00(m，1H)，6.15(m，1H)，3.91(d，J8Hz，2H)，1.92(d，J8Hz，3H)，0.92(d，J8Hz，6H)；LCMS：423[M+1]；c-MetKi：0.10μM。

Embodiment 23: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2,2-dimethyl--propyl group)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 1-iodo-2 according to program 5, and 2-dimethyl--propane is processed as alkylating reagent. ¹HNMR(400MHz，CDCl ₃)δ7.51(s，1H)，7.54(s，1H)，7.39(s，1H)，7.35(m，1H)，7.14(m，1H)，7.01(m，1H)，6.16(m，1H)，3.91(s，2H)，1.93(d，J8Hz，3H)，0.97(s，9H)；LCMS：437[M+1]；c-MetKi：0.12μM。

Embodiment 24: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(2-diethylin-ethyl)-isobutyramide

Title compound in the end uses N in the step according to program 5, N-diethylammonium ethane-1, and the 2-diamines is processed as amine. ¹HNMR(400MHz，CDCl ₃)δ7.69(s，1H)，7.65(m，1H)，7.52(s，1H)，7.40(m，1H)，7.31(s，1H)，7.21(m，1H)，7.15(m，1H)，7.09(m，1H)，7.00(m，1H)，6.19(m，1H)，3.69(m，2H)，3.40(m，2H)，3.21(m，4H)，2.81(m，6H)，1.93(d，2H)，1.80(s，6H)；LCMS ：551[M+1]；c-MetKi：0.22μM。

Embodiment 25: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(2-dimethylamino-ethyl)-isobutyramide

Title compound in the end uses N in the step according to program 5, N-dimethyl-ethane-1, and the 2-diamines is processed as amine. ¹HNMR(400MHz，CDCl ₃)δ7.68(m，2H)，7.63(s，1H)，7.30(m，1H)，7.07(m，1H)，6.95(m，1H)，6.86(m，1H)，6.07(m，1H)，3.45(m，2H)，2.79(m，2H)，2.50(s，6H)，2.05(s，3H)，1.85(m，9H)；LCMS：523[M+1]；c-MetKi：0.06μM。

Embodiment 26: 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-the pyrazol-1-yl methyl)-tetrahydrochysene-pyrans-4-alcohol

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4,5,5-tetramethyl--[1; 3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 4-(4-bromo-pyrazol-1-yl methyl)-tetrahydrochysene-pyrans-4-pure (according to general procedure 11, from 1,6-dioxa-spiral shell [2.5] octane begins to process). ¹HNMR(400MHz，CDCl ₃)δ7.67(s，1H)，7.59(s，1H)，7.45(s，1H)，7.31(m，1H)，7.08(m，1H)，6.86(s，1H)，6.07(m，1H)，5.43(m，2H)，4.08(s，2H)，3.77(m，5H)，2.09(s，3H)，1.86(d，2H)，1.62(m，3H)，1.37(m，2H)；LCMS：481[M+1]；c-MetKi：0.04μM。

Embodiment 27: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(tetrahydrochysene-furans-3-yl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine and 4-bromo-1-(tetrahydrochysene-furans-3-yl)-1H-pyrazoles (according to general procedure 11, beginning to process from tetrahydrochysene-furan-3-ol) process. ¹HNMR(400MHz，CDCl ₃)δ7.75(s，1H)，7.55(m，2H)，7.30(m，1H)，7.05(m，1H)，6.86(m，1H)，6.09(m，1H)，5.00(m，1H)，7.84(m，1H)，4.10(m，2H)，4.06(m，1H)，2.50(m，1H)，2.30(m，1H)，1.86(d，J8Hz，3H)；LCMS：437[M+1]；c-MetKi：0.04μM。

Embodiment 28: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(7-oxa--dicyclo also [2.2.1] heptan-the 2-ylmethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine and 4-bromo-1-(7-oxa--dicyclo also [2.2.1] heptan-the 2-ylmethyl)-the 1H-pyrazoles (according to general procedure 11, oneself (7-oxa--dicyclo also [2.2.1] heptan-the 2-yl)-methyl alcohol begins to process) process. ¹HNMR(400MHz，CDCl ₃)δ7.73(s，1H)，7.65(s，1H)，7.55(s，1H)，7.30(m，1H)，7.05(m，1H)，6.85(m，1H)，6.10(m，1H)，4.91(m，2H)，4.60(m，1H)，4.40(m，1H)，4.10(m，2H)，2.65(m，1H)，2.10(m，1H)，2.00(m，4H)，1.86(d，2H)，1.56(m，1H)，1.10(m，1H)；LCMS：477[M+1]；c-MetKi：0.06μM。

Embodiment 29: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(tetrahydrochysene-pyrans-4-yl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine and 4-bromo-1-(tetrahydrochysene-pyrans-4-yl)-1H-pyrazoles (according to general procedure 11, beginning to process from tetrahydrochysene-pyrans-4-alcohol) process. ¹HNMR(400MHz，CDCl ₃)δ7.55(m，1H)，7.50(m，1H)，7.47(m，1H)，7.40(m，1H)，7.14(m，1H)，7.03(m，1H)，6.17(m，1H)，4.35(m，1H)，4.12(m，2H)，3.57(m，2H)，2.10(m，4H)，1.94(d，3H)；LCMS：451[M+1]；c-MetKi：0.04μM。

Embodiment 30: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound is processed according to program 6. ¹HNMR(400MHz，CDCl ₃)δ7.65(s，1H)，7.54(s，1H)，7.50(s，1H)，7.40(m，1H)，7.15(m，1H)，7.02(s，1H)，6.15(m，1H)，4.45(m，1H)，3.56(m，2H)，3.15(m，2H)，2.35(m，4H)，1.93(d，J8Hz，3H)；LCMS：450[M+1]；c-MetKi：0.02μM。

Embodiment 31: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-((S)-1-tetramethyleneimine-3-base-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 3-((R)-4-bromo-pyrazol-1-yl)-tetramethyleneimine-1-carboxylic acid uncle-butyl ester (according to general procedure 11, oneself begins to process by (R)-3-hydroxyl-tetramethyleneimine-1-carboxylic acid uncle-butyl ester). ¹HNMR(400MHz，CDCl ₃)δ7.64(s，1H)，7.55(s，1H)，7.45(s，1H)，7.31(m，1H)，7.14(m，1H)，7.00(s，1H)，6.16(m，1H)，5.09(m，1H)，3.78(m，2H)，3.65(m，2H)，2.60(m，1H)，2.41(m，1H)，1.94(d，J8Hz，3H)；LCMS：436[M+1]；c-MetKi：0.03μM。

Embodiment 32: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(3-hydroxyl-propyl group)-isobutyramide

Title compound in the end uses the amino third-1-alcohol of 3-to process as amine according to program 5 in the step. ¹HNMR(400MHz，CDCl ₃)δ7.72(s，1H)，7.69(s，1H)，7.67(s，1H)，7.33(m，1H)，7.08(m，1H)，6.90(s，1H)，6.49(m，1H)，6.09(m，1H)，3.54(m，2H)，3.34(m，2H)，2.10(s，3H)，1.87(m，9H)，1.62(m，2H)；LCMS：510[M+1]；c-MetKi：0.07μM。

Embodiment 33: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-3-methyl-pyrazol-1-yl)-2-methyl-propionic acid

Title compound is according to program 5 (compounds 5-2) process. ¹HNMR(400MHz，CDCl ₃)δ7.54(s，1H)，7.51(s，1H)，7.50(m，1H)，7.49(m，2H)，6.01(m，1H)，5.03(bs，2H)，1.95(s，3H)，1.75(d，3H)，1.63(s，6H)；LCMS：467[M+1]；c-MetKi：0.13μM。

Embodiment 34: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(2-methoxyl group-ethyl)-isobutyramide

Title compound in the end uses (2-methoxy ethyl) amine to process as amine according to program 5 in the step. ¹HNMR(400MHz，CDCl ₃)δ7.73(s，1H)，7.69(s，1H)，7.66(s，1H)，7.31(m，1H)，7.08(m，1H)，7.05(s，1H)，6.45(m，1H)，6.10(m，1H)，5.10(m，2H)，3.36(s，3H)，3.25(m，4H)，1.87(m，9H)；LCMS：510[M+1]；c-MetKi：0.09μM。

Embodiment 35: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(2-hydroxyl-ethyl)-isobutyramide

Title compound in the end uses the 2-monoethanolamine to process as amine according to program 5 in the step. ¹HNMR(400MHz，CDCl ₃)δ7.75(s，1H)，7.70(s，1H)，7.67(s，1H)，7.31(m，1H)，7.09(m，1H)，6.89(s，1H)，6.56(m，1H)，6.08(m，1H)，5.0(m，2H)，3.65(m，2H)，3.36(m，2H)，1.87(m，9H)；LCMS：495[M+1]；c-MetKi：0.06μM。

Embodiment 36: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-3-methyl-pyrazol-1-yl)-N-(3-dimethylamino-propyl group)-isobutyramide

Title compound in the end uses N in the step according to program 5, N-dimethylpropane-1, and the 3-diamines is processed as amine. ¹HNMR(400MHz，CDCl ₃)δ7.60(s，1H)，7.48(s，1H)，7.30(m，1H)，7.08(m，1H)，6.73(s，1H)，6.04(m，1H)，6.15(m，2H)，3.28(m，2H)，2.59(m，4H)，2.38(s，6H)，2.20(s，3H)，2.05(s，3H)，1.86(d，J8Hz，3H)，1.81(s，6H)；LCMS：551[M+1]；c-MetKi：0.09μM。

Embodiment 37: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-3-methyl-pyrazol-1-yl)-N-(2-tetramethyleneimine-1-base-ethyl)-isobutyramide

Title compound in the end uses (2-tetramethyleneimine-1-base ethyl) amine to process as amine according to program 5 in the step. ¹HNMR(400MHz，CDCl ₃)δ7.59(s，1H)，7.48(s，1H)，7.30(m，1H)，7.07(m，2H)，6.04(m，1H)，5.10(m，2H)，3.48(m，2H)，3.00(m，6H)，2.18(s，3H)，2.06(s，3H)，1.93(m，4H)，1.84(d，J8Hz，3H)，1.82(s，6H)；LCMS：563[M+1]；c-MetKi：0.07μM。

Embodiment 38: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(1-sec.-propyl-piperidin-4-yl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 4-(4-bromo-pyrazol-1-yl)-1-sec.-propyl-piperidines (according to general procedure 11, use 2-iodo-propane is processed as alkylating reagent). ¹HNMR(400MHz，CDCl ₃)δ7.70(s，1H)，7.55(s，1H)，7.50(s，1H)，7.31(m，1H)，7.06(m，1H)，6.87(s，1H)，5.13(bs，2H)，4.16(m，1H)，3.13(m，2H)，2.94(m，1H)，2.30(m，9H)，2.07(s，3H)，1.86(d，J8Hz，3H)，1.13(d，J8Hz，6H)；LCMS：492[M+1]；c-MetKi：0.01μM。

Embodiment 39: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4,5,5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine and 4-(4-bromo-pyrazol-1-yl)-1-methyl-piperidines (processing according to general procedure 11) process. ¹HNMR(400MHz，CDCl ₃)δ7.70(s，1H)，7.56(s，1H)，7.49(s，1H)，7.29(m，1H)，7.06(m，1H)，6.87(s，1H)，6.08(m，1H)，5.17(bs，2H)，4.15(m，1H)，3.06(m，2H)，2.08(s，3H)，2.38(s，3H)，2.24(m，6H)，1.86(d，J8Hz，3H)；LCMS：464[M+1]；c-MetKi：0.01μM。

Embodiment 40: 1-[4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-yl]-2-hydroxyl-ethyl ketone

Title compound is processed according to program 7. ¹HNMR(400MHz，CDCl ₃)δ7.74(s，1H)，7.57(s，1H)，7.47(s，1H)，7.30(m，1H)，7.06(m，1H)，6.86(s，1H)，6.06(m，1H)，4.60(m，1H)，4.32(m，1H)，4.21(s，2H)，3.65(m，1H)，3.17(m，1H)，2.97(m，1H)，2.23(m，2H)，2.01(m，2H)，1.86(d，J8Hz，3H)；LCMS：508[M+1]；c-MetKi：0.01μM。

Embodiment 41: 1-[4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-yl]-ethyl ketone

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4,5,5-tetramethyl--[1; 3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 1-[4-(4-bromo-pyrazol-1-yl)-piperidines-1-yl]-ethyl ketone (exist to descend in triethylamine, in dichloromethane solvent, make from 4-(4-bromo-pyrazol-1-yl)-piperidines and Acetyl Chloride 98Min.). ¹HNMR(400MHz，CDCl ₃)δ7.71(s，1H)，7.57(s，1H)，7.47(s，1H)，7.30(m，1H)，7.07(m，1H)，6.87(s，1H)，6.07(m，1H)，5.08(bs，2H)，4.76(m，1H)，4.33(m，1H)，3.95(m，1H)，3.25(m，1H)，2.78(m，1H)，2.25(m，2H)，2.15(s，3H)，1.95(m，2H)，1.86(d，J8Hz，3H)；LCMS：492[M+1]；c-MetKi：0.01μM。

Embodiment 42: [4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-yl]-acetonitrile

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with [4-(4-bromo-pyrazol-1-yl)-piperidines-1-yl]-acetonitrile (according to general procedure 11, use 2-bromo-acetonitrile is processed as alkylating reagent). ¹HNMR(400MHz，CDCl ₃)δ7.75(s，1H)，7.57(s，1H)，7.49(s，1H)，7.30(m，1H)，7.06(m，1H)，6.87(s，1H)，6.08(m，1H)，4.85(bs，2H)，4.13(m，1H)，3.60(s，2H)，2.94(m，2H)，2.56(m，2H)，2.20(m，2H)，2.13(m，2H)，1.86(d，J8Hz，3H)；LCMS：489[M+1]；c-MetKi：0.02μM。

Embodiment 43: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(1-ethyl-piperidin-4-yl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 4-(4-bromo-pyrazol-1-yl)-1-ethyl-piperidines (according to general procedure 11, use 1-ethyl iodide is processed as alkylating reagent). ¹HNMR(400MHz，CDCl ₃)δ7.71(s，1H)，7.55(s，1H)，7.50(s，1H)，7.31(m，1H)，7.05(m，1H)，6.87(s，1H)，6.07(m，1H)，5.08(bs，2H)，4.15(m，1H)，3.14(m，2H)，2.51(m，2H)，2.19(m，6H)，2.08(s，3H)，1.86(d，J8Hz，3H)，1.14(m，3H)；LCMS：478[M+1]；c-MetKi：0.01μM。

Embodiment 44: 1-[4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-yl]-2-dimethylamino-ethyl ketone

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4,5,5-tetramethyl--[1; 3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 1-[4-(4-bromo-pyrazol-1-yl)-piperidines-1-yl]-2-dimethylamino-ethyl ketone (in the DMF solvent, use HOBt/EDC/ triethylamine is made from 4-(4-bromo-pyrazol-1-yl)-piperidines and dimethylamino-acetate). ¹HNMR(400MHz，CDCl ₃)δ7.67(s，1H)，7.56(s，1H)，7.47(s，1H)，7.30(m，1H)，7.07(m，1H)，6.67(s，1H)，6.07(m，1H)，5.31(bs，2H)，4.70(m，1H)，4.33(m，2H)，3.20(m，4H)，2.79(m，1H)，2.33(s，6H)，2.20(m，2H)，2.08(s，3H)，1.92(m，1H)，1.86(d，J8Hz，3H)；LCMS：535[M+1]；c-MetKi：0.01μM。

Embodiment 45: 5-[1-(1-cyclopropyl methyl-piperidin-4-yl)-1H-pyrazoles-4-yl]-3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 4-(4-bromo-pyrazol-1-yl)-1-cyclopropyl methyl-piperidines (according to general procedure 11, use iodomethyl-Trimetylene is processed as alkylating reagent). ¹HNMR(400MHz，CDCl ₃)δ7.62(s，1H)，7.54(m，2H)，7.37(m，1H)，7.16(m，1H)，7.06(s，1H)，7.01(s，1H)，6.18(m，1H)，4.50(m，1H)，3.98(m，1H)，3.69(m，1H)，3.50(m，1H)，3.02(m，2H)，2.95(m，1H)，2.65(m，2H)，2.44(m，1H)，2.31(m，1H)，1.94(m，3H)，1.14(m，1H)，0.80(m，2H)，0.42(m，2H)；LCMS：504[M+1]；c-MetKi：0.01μM。

Embodiment 46: 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound is according to program 6, uses 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4; 4,5,5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine and 4-(4-bromo-pyrazol-1-yl)-1-methyl-piperidines (processing according to general procedure 11) process. ¹HNMR(400MHz，CDCl ₃)δ7.65(s，1H)，7.55(s，1H)，7.50(s，1H)，7.31(m，1H)，7.06(m，1H)，6.87(s，1H)，6.08(m，1H)，5.50(bs，2H)，4.18(m，1H)，3.11(m，2H)，2.40(s，3H)，2.30(m，2H)，2.20(m，4H)，2.07(s，3H)，1.86(d，J8Hz，3H)；LCMS：464[M+1]；c-MetKi：0.01μM。

Embodiment 47: 1-[4-(4-{6-amino-5-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-yl]-2-hydroxyl-ethyl ketone

Title compound is processed according to program 7. ¹HNMR(400MHz，CDCl ₃)δ7.72(s，1H)，7.57(s，1H)，7.47(s，1H)，7.31(m，1H)，7.06(m，1H)，6.86(s，1H)，6.08(m，1H)，5.00(bs，2H)，4.70(m，1H)，4.36(m，1H)，4.21(s，1H)，3.70(m，1H)，3.18(m，1H)，3.00(m，1H)，2.223(m，2H)，2.01(m，2H)，1.86(d，J8Hz，3H)；LCMS：508[M+1]；c-MetKi：0.004μM。

Embodiment 48: 5-(1-cyclopentyl-1H-pyrazoles-4-yl)-3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 4-(4-bromo-pyrazol-1-yl)-1-cyclopentyl-piperidines (according to general procedure 11, use bromine pentamethylene is processed as alkylating reagent). ¹HNMR(400MHz，CDCl ₃)δ7.75(s，1H)，7.55(s，1H)，7.48(s，1H)，7.28(m，1H)，7.05(m，1H)，6.87(s，1H)，6.07(m，1H)，4.81(bs，2H)，4.64(m，1H)，2.18(m，2H)，2.05(m，2H)，1.86(m，3H)，1.71(m，4H)；LCMS：435[M+1]；c-MetKi：0.04μM。

Embodiment 49: 5-(1-cyclobutyl-1H-pyrazoles-4-yl)-3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 4-(4-bromo-pyrazol-1-yl)-1-cyclobutyl-piperidines (according to general procedure 11, use bromine pentamethylene is processed as alkylating reagent). ¹HNMR(400MHz，CDCl ₃)δ7.74(s，1H)，7.57(s，1H)，7.50(s，1H)，7.28(m，1H)，7.05(m，1H)，6.87(s，1H)，6.08(m，1H)，4.90(bs，2H)，4.75(m，1H)，2.51(m，4H)，1.88(m，5H)；LCMS：421[M+1]；c-MetKi：0.02μM。

Embodiment 50: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(1-methane sulfonyl-piperidin-4-yl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyridine-2-base amine and Methanesulfonyl chloride to process according to program 7. ¹HNMR(400MHz，CDCl ₃)δ7.75(s，1H)，7.57(s，1H)，7.49(s，1H)，7.31(m，1H)，7.06(m，1H)，6.08(m，1H)，4.82(bs，2H)，4.26(m，1H)，3.94(m，2H)，2.98(m，2H)，2.85(s，3H)，2.26(m，2H)，2.18(m，2H)，1.86(d，J8Hz，3H)；LCMS ：528[M+1]；c-MetKi：0.01μM。

Embodiment 51: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidines-3-base-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4,5,5-tetramethyl--[1; 3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine and 4-(4-bromo-pyrazol-1-yl)-[1,3 '] two piperidyls-1 '-carboxylic acid uncle-butyl ester (according to general procedure 11, use 3-hydroxy-piperdine-1-carboxylic acid uncle-butyl ester is processed) processes. ¹HNMR(400MHz，CDCl ₃)δ7.69(s，1H)，7.55(s，1H)，7.52(s，1H)，7.31(m，1H)，7.07(m，1H)，6.86(s，1H)，6.07(m，1H)，5.21(bs，2H)，4.26(m，1H)，3.40(m，1H)，3.07(m，2H)，2.77(m，1H)，2.11(m，4H)，2.08(s，3H)，1.86(d，J8Hz，3H)；LCMS：450[M+1]；c-MetKi：0.01μM。

Embodiment 52: 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound is according to program 6, uses 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 4-(4-bromo-pyrazol-1-yl)-1-cyclopentyl-piperidines (according to general procedure 11, use bromine pentamethylene is processed as alkylating reagent). ¹HNMR(400MHz，CDCl ₃)δ7.73(s，1H)，7.55(s，1H)，7.48(s，1H)，7.31(m，1H)，7.07(m，1H)，6.88(s，1H)，6.08(m，1H)，4.64(m，1H)，2.04(m，2H)，1.98(m，2H)，1.86(d，J8Hz，3H)，1.73(m，2H)；LCMS：435[M+1]；c-MetKi：0.02μM。

Embodiment 53: 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound is processed according to program 6. ¹HNMR(400MHz，CDCl ₃)δ7.69(s，1H)，7.56(s，1H)，7.50(s，1H)，7.32(m，1H)，7.07(m，1H)，6.87(m，1H)，6.07(m，1H)，5.25(bs，2H)，4.30(m，1H)，3.41(m，2H)，2.96(m，2H)，2.26(m，2H)，2.12(m，2H)，1.86(d，J8Hz，3H)；LCMS：450[M+1]；c-MetKi：0.003μM。

Embodiment 54: 3-(3-fluoro-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-5-base oxygen base)-5-(1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound uses 5-bromo-3-(3-fluoro-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-5-base oxygen base)-pyridine-2-base amine and 4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-1H-pyrazoles to process according to program 6. ¹HNMR (400MHz, DMSO-d6) δ 7.09 (s, 2H), 6.86 (s, 1H), 6.66 (s, 1H), 6.38 (t, 1H); 6.25 (dd, 1H), 6.08 (dt, 1H), 5.03 (d, 1H), 2.16 (t, 2H), 1.42 (m; 1H), 1.33 (br, 1H), 1.19 (br, 2H), 1.07 (br, 1H), 0.66 (br, 1H); LCMS:339 [M+1]; C-Met% suppresses: 21% μ M.

Embodiment 55: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N, N-diethylammonium-isobutyramide

Title compound in the end uses diethylamine to process as amine according to program 5 in the step. ¹HNMR(400MHz，DMSO-d6)δ7.96(s，1H)，7.78(d，1H)，7.61(s，1H)，7.45(q，1H)，7.42(t，1H)，6.90(d，1H)，6.09(q，1H)，5.68(s，2H)，4.09(q，1H)，3.20(m，1H)，3.16(d，2H)，2.81(m，1H)，1.80(d，3H)，1.66(s，6H)，1.18(m，1H)，1.10(t，1H)，1.01(br，2H)，0.60(br，2H)；LCMS：508[M+1]；c-MetKi：0.3964μM。

Embodiment 56: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-1-((S)-3-hydroxyl-tetramethyleneimine-1-yl)-2-methyl-third-1-ketone

Title compound in the end uses (3S)-tetramethyleneimine-3-alcohol to process as amine according to program 5 in the step. ¹HNMR(400MHz，DMSO-d6)δ8.32(d，1H)，7.97(br，1H)，7.81(s，1H)，7.72(s，1H)，7.59(q，1H)，7.47(t，1H)，7.18(t，1H)，6.29(d，1H)，4.10(br，1H)，4.00(br，1H)，3.59(m，2H)，3.42(m，2H)，2.31(m，1H)，1.85(d，3H)，1.75(m，3H)，1.70(d，5H)，1.63(m，2H)；LCMS：522[M+1]；c-MetKi：0.47μM。

Embodiment 57: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-2-methyl isophthalic acid-tetramethyleneimine-1-base-third-1-ketone

Title compound in the end uses tetramethyleneimine to process as amine according to program 5 in the step. ¹HNMR(400MHz，DMSO-d6)δ8.04(s，1H)，7.80(s，1H)，7.61(s，1H)，7.55(q，1H)，7.43(t，1H)，6.92(s，1H)，6.10(q，1H)，5.67(s，2H)，2.37(m，1H)，1.79(d，3H)，1.66(s，6H)，1.59(m，4H)；LCMS：506[M+1]；c-MetKi：0.425μM。

Embodiment 58: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N, N-dimethyl--isobutyramide

Title compound in the end uses n n dimetylaniline to process as amine according to program 5 in the step. ¹HNMR(400MHz，DMSO-d6)δ8.16(d，1H)，7.79(d，1H)，7.70(d，1H)，7.45(q，1H)，7.11(s，1H)，6.25(t，1H)，1.80(d，3H)，1.66(s，6H)；LCMS：480[M+1]；c-MetKi：0.125μM。

Embodiment 59: 2-(4-[6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl]-pyrazol-1-yl)-2-methyl-third-1-alcohol

Title compound is processed according to program 8. ¹HNMR(400MHz，DMSO-d6)δ7.90(s，1H)，7.75(s，1H)，7.52(m，1H)，7.51(s，1H)，7.43(t，1H)，6.87(s，1H)，6.06(q，1H)，5.61(s，2H)，4.93(br，1H)，3.54(s，2H)，1.80(d，3H)，1.44(s，6H)；LCMS：439[M+1]；c-MetKi：0.014μM。

Embodiment 60: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2-dimethylamino-1,1-dimethyl--ethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound is processed according to program 8, use 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N, N-dimethyl--isobutyramide supplies reduction. ¹HNMR(400MHz，DMSO-d6)δ7.88(s，1H)，7.76(s，1H)，7.53(m，2H)，7.43(t，1H)，6.87(s，1H)，6.06(q，1H)，5.62(s，2H)，1.80(s，6H)，1.78(d，3H)，1.48(s，6H)；LCMS：466[M+1]；c-MetKi：0.084μM。

Embodiment 61: (S)-1-[2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-2-methyl-propyl group]-tetramethyleneimine-3-alcohol

Title compound is processed according to program 8, use 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-1-((S)-3-hydroxyl-tetramethyleneimine-1-yl)-2-methyl-third-1-ketone confession reduction. ¹HNMR(400MHz，DMSO-d6)δ7.88(s，1H)，7.76(s，1H)，7.54(m，2H)，7.43(t，1H)，6.87(s，1H)，6.08(q，1H)，5.62(s，2H)，4.52(br，1H)，4.00(br，1H)，2.75(br，2H)，2.34(br，1H)，2.20(br，1H)，2.06(br，1H)，1.90(d，2H)，1.80(d，3H)，1.49(s，6H)，1.39(br，1H)；LCMS：508[M+1]；c-MetKi：0.07μM。

Embodiment 62: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-{1-[1,1-dimethyl--2-(2-tetramethyleneimine-1-base-oxyethyl group)-ethyl]-1H-pyrazoles-4-yl }-pyridine-2-base amine

Title compound uses 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 6; 4,5,5-tetramethyl--[1; 3; 2] dioxane pentaborane-2-yl)-and pyridine-2-base amine and 4-bromo-1-[1,1-dimethyl--2-(2-tetramethyleneimine-1-base-oxyethyl group)-ethyl]-1H-pyrazoles process, and it is processed by following:

In the solution of 2-(4-bromo-pyrazol-1-yl)-2-methyl-methyl propionate (5.00 grams, 20.2 mmoles) in anhydrous THF (67 milliliters), under nitrogen, dropwise add LiAlH ₄(1.0M, in THF, 22.3 milliliters).With reaction mixture stirred overnight under nitrogen and envrionment temperature, and, in ice bath,, make the reaction cancellation to pH5 with HCl solution (2N).With product with ethyl acetate extraction.With the extract that merges with water, brine wash, and with Na ₂SO ₄Drying is to provide 2-(4-bromo-pyrazol-1-yl)-2-methyl-third-1-alcohol (3.022 grams, 68% yield).

In the solution of 2-(4-bromo-pyrazol-1-yl)-2-methyl-third-1-alcohol (0.50 gram, 2.28 mmoles) and 1-(2-chloro-ethyl)-tetramethyleneimine (0.3072 gram, 2.28 mmoles), interpolation NaH (60%, in Dormant oils, 27.4 mmoles).To react under nitrogen and the envrionment temperature and stir 0.5 hour, under 70 ℃, spend the night then.After being cooled to envrionment temperature, make the reaction cancellation through adding water.With product with ethyl acetate extraction, and with extract with water, brine wash, and with Na ₂SO ₄Dry.Make crude product purifying on reversed-phase column, so that 4-bromo-1-[1,1-dimethyl--2-(2-tetramethyleneimine-1-base-oxyethyl group)-ethyl]-1H-pyrazoles (97.8 milligrams, 18% yield) to be provided.

3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-{1-[1,1-dimethyl--2-(2-tetramethyleneimine-1-base-oxyethyl group)-ethyl]-1H-pyrazoles-4-yl }-pyridine-2-base amine: ¹HNMR (400MHz, DMSO-d6) δ 7.95 (s, 1H), 7.56 (dd, 2H), 7.41 (m, 1H), 7.22 (t, 1H), 7.08 (s; 1H), 6.26 (q, 1H), 3.68 (s, 2H), 3.56 (t, 2H), 3.35 (m, 2H), 2.87 (m; 2H), 2.57 (d, 2H), 1.85 (m, 6H), 1.53 (s, 6H), 1.20 (d, 1H); LCMS: 536 [M+1]; C-MetKi:0.229 μ M.

Embodiment 63: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-(R)-1-tetramethyleneimine-2-ylmethyl-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound is according to program 11, and then according to program 6, [1-(2 to use 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4,5; 5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 2-[(R) 4-(4-bromo-pyrazol-1-yl)-piperidines-1-ylmethyl]-tetramethyleneimine-1-carboxylic acid uncle-butyl ester (according to general procedure 11, use (R)-2-methylol-tetramethyleneimine-1-carboxylic acid uncle-butyl ester is processed). ¹HNMR(400MHz，DMSO-d6)δ9.95(br，2H)，8.68(d，1H)，8.50(br，1H)，8.34(s，1H)，8.27(d，1H)，8.12(m，1H)，7.99(t，1H)，7.65(s，1H)，6.76(q，1H)，6.26(s，2H)，5.05(br，2H)，4.40(br，1H)，3.74(m，2H)，2.56(m，1H)，2.36(d，3H)，2.16(m，1H)；LCMS：450[M+1]；c-MetKi：0.072μM。

Embodiment 64: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-(S)-1-tetramethyleneimine-2-ylmethyl-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound is according to program 11, and then according to program 6, [1-(2 to use 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4,5; 5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 2-[(S) 4-(4-bromo-pyrazol-1-yl)-piperidines-1-ylmethyl]-tetramethyleneimine-1-carboxylic acid uncle-butyl ester (according to general procedure 11, use (S)-2-methylol-tetramethyleneimine-1-carboxylic acid uncle-butyl ester is processed). ¹HNMR(400MHz，DMSO-d6)δ7.86(s，1H)，7.72(s，1H)，7.56(m，1H)，7.51(d，1H)，6.86(s，1H)，6.06(q，1H)，5.64(s，2H)，3.96(d，2H)，2.76(m，2H)，1.79(d，6H)，1.60(m，3H)，1.33(m，1H)；LCMS：450[M+1]；c-MetKi：0.0415μM。

Embodiment 65: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-((R)-1-tetramethyleneimine-3-base-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound is according to program 11, and then according to program 6, [1-(2 to use 3-; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4,5; 5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes with 3-((S)-4-bromo-pyrazol-1-yl)-tetramethyleneimine-1-carboxylic acid uncle-butyl ester (according to general procedure 11, oneself begins to process by (S)-3-hydroxyl-tetramethyleneimine-1-carboxylic acid uncle-butyl ester). ¹HNMR(400MHz，DMSO-d6)δ7.93(s，1H)，7.74(d，1H)，7.55(m，1H)，7.51(s，1H)，7.43(t，1H)，6.87(d，1H)，6.06(q，1H)，5.64(s，2H)，4.75(m，1H)，3.11(m，1H)，3.01(m，1H)，2.94(m，1H)，2.85(m，1H)，2.15(m，1H)，1.99(m，1H)，1.87(s，3H)，1.78(d，3H)；LCMS：436[M+1]；c-MetKi：0.298μM。

Embodiment 66: 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyrazine-2-base amine

Title compound is processed according to program 12. ¹HNMR(400MHz，DMSO-d6)δ7.86(s，1H)，7.76(s，1H)，7.63(m，2H)，7.54(m，1H)，7.37(t，1H)，6.46(q，1H)，6.15(s，1H)，4.10(m，1H)，3.01(m，2H)，1.95(m，2H)，1.85(s，2H)，1.75(d，3H)，1.67(dd，1H)；LCMS：451[M+1]；c-MetKi：0.010μM。

Embodiment 67: 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1H-pyrazoles-4-yl)-pyrazine-2-base amine

Title compound is according to program 10, uses 5-bromo-3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-base amine and 4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-pyrazoles-1-carboxylic acid uncle-butyl ester to process. ¹HNMR(400MHz，DMSO-d6)δ12.81(s，1H)，7.79(s，1H)，7.48(m，1H)，7.36(t，1H)，6.48(q，1H)，6.12(s，2H)，1.75(d，3H)；LCMS：368[M+1]；c-MetKi：0.065μM。

Embodiment 68: 1-[4-(4-{5-amino-6-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-yl }-pyrazol-1-yl)-piperidines-1-yl]-2-hydroxyl-ethyl ketone

Title compound is according to program 6 and 7, uses 5-bromo-3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-base amine to process as raw material. ¹HNMR(400MHz，DMSO-d6)δ7.91(s，1H)，7.76(s，1H)，7.64(s，1H)，7.49(m，1H)，7.36(t，1H)，6.46(q，1H)，6.15(s，2H)，4.57(br，1H)，4.40(m，2H)，4.12(br，2H)，3.77(m，1H)，3.35(m，2H)，3.43(m，1H)，3.16(m，2H)，1.75(d，3H)；LCMS：509[M+1]；c-MetKi：0.015μM。

Embodiment 69: 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazoles-4-yl]-pyrazine-2-base amine

Title compound is according to program 6, uses 5-bromo-3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-base amine and 4-(4-bromo-pyrazol-1-yl)-1-methyl-piperidines (processing according to general procedure 11) to process. ¹HNMR(400MHz，DMSO-d6)δ7.88(s，1H)，7.76(s，1H)，7.64(s，1H)，7.49(m，1H)，7.36(t，1H)，6.46(q，1H)，6.15(s，2H)，4.02(m，1H)，2.84(m，2H)，2.19(s，3H)，2.00(m，4H)，1.85(m，3H)，1.75(d，3H)；LCMS：465[M+1]；c-MetKi：0.03μM。

Embodiment 70: 1-[4-(4-{5-amino-6-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-yl }-pyrazol-1-yl)-piperidines-1-yl]-2-dimethylamino-ethyl ketone

Title compound is processed according to program 7; Use 3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyrazine-2-base amine and dimethylamino-acetate coupling, exist down in the HOBt/EDC/ triethylamine; In DMF; Described in the follow procedure 5, use 5-bromo-3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyrazine-2-base amine as raw material. ¹HNMR(400MHz，DMSO-d6)δ7.90(s，1H)，7.76(s，1H)，7.65(s，1H)，7.49(m，1H)，7.36(t，1H)，6.47(q，1H)，6.15(s，2H)，4.39(m，1H)，4.16(m，1H)，3.16(m，2H)，3.02(m，1H)，2.75(m，1H)，2.19(s，6H)，2.01(m，2H)，1.88(s，1H)，1.75(d，3H)；LCMS ：536[M+1]；c-MetKi：0.015μM。

Embodiment 71: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-methane sulfonyl-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound is according to program 5, uses 5-bromo-3-[(R)-1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine and 1-methane sulfonyl-4-(4,4; 5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-the 1H-pyrazoles is (in the triethylamine existence down; In dichloromethane solvent, system from the 4-(4,4,5 of Methanesulfonyl chloride reaction; 5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-and the 1H-pyrazoles) process. ¹HNMR(400MHz，CDCl ₃)δ8.41(s，1H)，8.13(s，1H)，7.89(d，1H)，7.51(dd，1H)，7.38(t，1H)，7.07(d，1H)，6.09(q，1H)，5.79(bs，2H)，3.49(s，3H)，1.74(d，3H)；LCMS：445[M+1]；c-MetKi：0.17μM。

Embodiment 72: 3-[(R)-1-(2-chloro-3,6-two fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound is according to program 6; Use 5-bromo-3-[(R)-1-(2-chloro-3; 6-two fluoro-phenyl)-oxyethyl group]-pyridine-2-base amine as raw material (according to (S)-1-(the 2-chloro-3 that obtains from SynChem company; 6-two fluoro-phenyl)-and the method for the synthetic 5-bromo-3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group] of ethanol-pyridine-2-base amine) process. ¹HNMR(400MHz，DMSO-D6)δ7.88(s，1H)，7.70(s，1H)，7.50(s，1H)，7.38(m，1H)，7.25(m，1H)，6.99(s，1H)，5.88(m，1H)，5.48(bs，2H)，4.08(m，1H)，2.96(m，2H)，2.53(m，1H)，2.45(m，1H)，1.89(m，1H)，1.80(m，4H)，1.67(m，4H)；LCMS：434[M+1]；c-MetKi：0.09μM。

Embodiment 73: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2-methylamino--ethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound then according to program 14, uses [2-(4-bromo-pyrazol-1-yl)-ethyl]-methyl-carboxylamine uncle-butyl ester as aryl halide, and processes according to program 13 according to program 16. ¹HNMR (400MHz, δ ppm 7.75 (d, J=1.77Hz, 1H) 7.58 (s, 1H) 7.50 (s, 1H) 7.30 (dt of chloroform-D); J=9.16,4.64Hz, 1H) 7.05 (dd, J=8.84,7.83Hz, 1H) 6.86 (d; J=1.77Hz, 1H) 6.07 (q, J=6.74Hz, 1H) 4.83 (s, 2H) 4.22-4.30 (m; 2H) 3.08-3.13 (m, 2H) 2.49 (s, 3H) 1.86 (d, J=6.82Hz, 3H); LCMS:424 [M+1]; C-MetKi:0.055 μ M.

Embodiment 74: 2-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-N-(3-dimethylamino-propyl group)-propionic acid amide

Title compound then according to 14, uses 2-(4-bromo-pyrazol-1-yl)-N-(3-dimethylamino-propyl group)-propionic acid amide as aryl halide, then according to program 18, then for processing according to program according to program 17. ¹HNMR (400MHz, δ ppm7.78 (s, 1H) 7.66 (s, 1H) 7.55 (s, 1H) 7.46-7.53 (m, 1H) 7.31 (dd, J=8.72, the 4.93Hz of chloroform-D); 1H) 7.06 (t, J=8.46Hz, 1H) 6.87 (s, 1H) 6.07 (q, J=6.48Hz, 1H) 4.90 (q, J=7.41Hz; 1H) 4.80 (s, 2H) 3.31 (q, J=5.64Hz, 2H) 2.27 (t, J=5.81Hz, 2H) 2.02 (s, 6H) 1.86 (d; J=6.57Hz, and 3H) 1.80 (d, J=7.33Hz, 3H) 1.57 (dt, J=12.06,5.97Hz, 2H); LCMS:523 [M+1]; C-MetKi:0.04 μ M.

Embodiment 75: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazole-3-yl)-pyridine-2-base amine

Title compound is according to program 14, uses 4-(3-iodo-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester, then removes the protection base and processes.In 70 milligrams of 4-(3-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester, at room temperature, add 3 milliliters of methylene dichloride, then add 1 milliliter of trifluoroacetic acid.After stirring 2 hours, reaction is accomplished.Through the reversed-phase HPLC purifying, obtain 80 milligrams of white water absorbability solids.Through being dissolved in the methylene dichloride, and accomplishing with the sodium hydrogencarbonate washing and to change into free alkali, it causes 17 milligrams of white solid 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazole-3-yl)-pyridine-2-base amine. ¹HNMR(400MHz，DMSO-D6)δppm7.87(d，J＝1.77Hz，1H)7.68(d，J＝2.27Hz，1H)7.53(m，1H)7.42(m，1H)7.09(d，J＝1.77Hz，1H)6.34(d，J＝2.27Hz，1H)6.04(q，J＝6.82Hz，1H)5.77(s，2H)4.10(m，1H)3.03(m，2H)2.58(m，2H)1.91(m，2H)1.79(d，J＝6.82Hz，3H)1.75(m，2H)；LCMS：450[M+1]；c-MetKi：0.038μM。

Raw material 4-(3-iodo-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester is processed by following:

1-(2-TMS-ethoxyl methyl)-1H-pyrazoles: in the 4.9 gram 95%NaH in Dormant oils, add 200 milliliters of THF.Dropwise add 50 milliliters of pyrazoles (12 gram) among the THF, and under room temperature, stirred 1 hour.After being cooled to 0 ℃, dropwise add the solution of 34.32 milliliters of SEMCl in 50 milliliters of THF.Remove cooling bath, and will react stirred overnight at room temperature.Make the reaction cancellation with water, concentrate, with the ether dilution, and with ammonium chloride, brine wash, and with dried over sodium sulfate.With 20-30%EtOAc/ hexane chromatography, cause 12 gram products. ¹HNMR (400MHz, the δ ppm 7.55 of chloroform-D) (dd, J=5.81,1.77Hz, 2H) 6.33 (t, J=2.02Hz, 1H) 5.44 (s, 2H) 3.50-3.58 (m, 2H) 0.85-0.95 (m, 2H) 0.04 (s, 9H).

5-iodo-1-(2-TMS-ethoxyl methyl)-1H-pyrazoles: in 2.0 gram 1-(2-TMS-ethoxyl methyl)-1H-pyrazoles in 40 milliliters of THF, under-78 ℃, dropwise add 4.43 milliliters of 2.5N nBuLi.With solution restir 45 minutes.Dropwise add 20 milliliters of iodine (7.67 gram) among the THF then.After all iodine add, remove cooling bath, and make mixture be warmed to room temperature, went through 2 hours.Through adding several milliliters NH ₄The Cl aqueous solution (saturated) makes the reaction cancellation.Make solution concentration, with the ether dilution, with sodium sulfite aqueous solution, water, brine wash, and with dried over sodium sulfate.With 5-10%EtOAc/ hexane chromatography, obtain 1.66 gram products, be oily matter. ¹HNMR (400MHz, the δ ppm7.53 of chloroform-D) (d, J=1.77Hz, 1H) 6.49 (d, J=1.77Hz, 1H) 5.50 (s, 2H) 3.53-3.61 (m, 2H) 0.86-0.95 (m, 2H) 0.04 (m, 9H).

5-iodo-1H-pyrazoles: in 1.0 gram 5-iodo-1-(2-TMS-ethoxyl methyl)-1H-pyrazoles, under 0 ℃, add the mixture of 1.72 milliliters of triethyl silicanes and 4 milliliters of TFA.After adding, remove cooling bath.Under 1.5 hours, remove and desolvate, stay 570 milligrams of white solids. ¹HNMR (400MHz, the δ ppm7.53 of chloroform-D) (m, and 1H) 6.51 (m, 1H).

4-(3-iodo-pyrazol-1-yl)-piperidines-1-carboxylic acid uncle-butyl ester: in 500 milligrams of 5-iodo-1H-pyrazoles in 3 milliliters of DMF, add 54 milligrams of 95%NaH.It was at room temperature stirred 5 minutes, then heated 30 minutes down at 80 ℃.Make solution be cooled to room temperature, and add 417 milligrams of BOC piperidines methane sulfonates.Reaction is heated to 90 ℃ spends the night.Learn through TLC to still have some iodo-pyrazoles, therefore add 100 milligrams of methane sulfonates again, and reheat 18 hours.Make reaction cooled, and in vacuum, remove a part of DMF.Solution is diluted with ETHYLE ACETATE, and with sodium hydrogencarbonate, brine wash, and with dried over sodium sulfate.Remove and desolvate, cause clean oil.With 5,10,20%EtOAc/CH ₂Cl ₂Chromatography causes 180 milligrams of products, is clean oil. ¹HNMR (400MHz, the δ ppm7.23 of chloroform-D) (d, J=2.27Hz, 1H) 6.40 (d, J=2.27Hz, 1H) 4.24 (m, 3H) 2.84 (s, 2H) 2.02-2.12 (m, 2H) 1.87 (m, 2H) 1.40-1.47 (m, 9H).

Embodiment 76: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1H-pyrazole-3-yl)-pyridine-2-base amine

Title compound is according to program 10, uses 3-iodo-1-(2-TMS-ethoxyl methyl)-1H-pyrazoles, then removes 2-TMS-ethoxyl methyl and processes.In 60 milligrams of 3-in 1 milliliter of methylene dichloride [1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2-TMS-ethoxyl methyl)-1H-pyrazole-3-yl]-pyridine-2-base amine, add 60 microlitre triethyl silicanes and 0.5 milliliter of trifluoroacetic acid.After at room temperature stirring 4 hours, add 3 milliliters of toluene, and in vacuum, remove and desolvate.Residue is dissolved among the EtOAc, and washs with sodium hydrogencarbonate.With 10%MeOH/40%EtOAc/50%CH ₂Cl ₂Chromatography obtains 20 milligrams of white solids. ¹HNMR(400MHz，DMSO-D6)δppm7.92(d，J＝1.52Hz，1H)7.68(s，1H)7.49-7.59(m，1H)7.43(t，J＝8.72Hz，2H)7.12(s，1H)6.41(s，1H)6.06(s，1H)5.90(s，2H)3.32(s，4H)1.78(d，J＝6.57Hz，3H)；LCMS：367[M+1]；c-MetKi：0.035μM。

Embodiment 77: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(3-methyl-pyrazol-1-yl)-pyridine-2-base amine

Title compound is processed according to program 19. ¹HNMR(400MHz，DMSO-D6)δppm8.07(d，J＝2.27Hz，1H)7.90(d，J＝2.02Hz，1H)7.57(dd，J＝9.09，5.05Hz，1H)7.46(t，J＝8.72Hz，1H)7.33(d，J＝1.77Hz，1H)6.27(d，J＝2.27Hz，1H)6.17(q，J＝6.48Hz，1H)2.20(s，3H)1.82(d，J＝6.57Hz，3H)；LCMS：381[M+1]；c-MetKi：1.92μM。

Embodiment 78: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-indazole-1-base-pyridine-2-base amine

Title compound uses the 1H-indazole to replace 3-methyl isophthalic acid H-pyrazoles to process according to program 19. ¹HNMR(400MHz，DMSO-D6)δppm8.29(s，1H)7.83-7.89(m，2H)7.58-7.63(m，1H)7.52(t，J＝8.72Hz，1H)7.39(t，J＝7.71Hz，1H)7.17-7.26(m，2H)7.00(d，J＝2.02Hz，1H)6.14(q，J＝6.40Hz，1H)1.82(d，J＝6.57Hz，3H)；LCMS：417[M+1]；c-MetKi：1.56μM。

Embodiment 79: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-pyrazol-1-yl-pyridine-2-base amine

Title compound uses pyrazoles to replace 3-methyl isophthalic acid H-pyrazoles to process according to program 19. ¹HNMR(400MHz，DMSO-D6)δppm8.21(d，J＝2.53Hz，1H)7.95(d，J＝2.02Hz，1H)7.67(d，J＝1.77Hz，1H)7.57(dd，J＝8.97，4.93Hz，1H)7.45(t，J＝8.72Hz，1H)7.29(d，J＝1.77Hz，1H)6.46-6.52(m，1H)6.16(t，J＝6.57Hz，1H)1.81(d，J＝6.57Hz，3H)；LCMS：367[M+1]；c-MetKi：0.87μM。

Embodiment 80: 1-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-1H-pyrazoles-4-carboxylic acid, ethyl ester

Title compound uses 1H-pyrazoles-4-carboxylic acid, ethyl ester to replace 3-methyl isophthalic acid H-pyrazoles to process according to program 19. ¹HNMR(400MHz，DMSO-D6)δppm8.81(s，1H)8.02-8.08(m，2H)7.56(dd，J＝9.09，5.05Hz，1H)7.45(t，J＝8.84Hz，1H)7.29(d，J＝2.02Hz，1H)6.14(q，J＝6.57Hz，1H)4.24(q，J＝7.07Hz，3H)1.80(d，J＝6.57Hz，3H)1.26(q，J＝7.58Hz，4H)；LCMS：439[M+1]；c-MetKi：2.05μM。

Embodiment 81: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-piperidin-4-yl methyl isophthalic acid H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound uses 4-(4-bromo-pyrazol-1-yl methyl)-piperidines-1-carboxylic acid uncle-butyl ester (utilizing general procedure 11 to process) and 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 15; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-and pyridine-2-base amine, then removal is protected (general procedure 3) and is processed. ¹HNMR(400MHz，DMSO-D6)δppm8.51(s，1H)8.20(s，1H)7.99(s，1H)7.72(d，J＝1.52Hz，1H)7.65(s，1H)7.59(dd，J＝8.97，4.93Hz，1H)7.47(t，J＝8.72Hz，1H)7.06(s，1H)6.23(q，J＝6.48Hz，1H)4.04(d，J＝6.82Hz，3H)3.68-3.78(m，1H)3.44-3.54(m，2H)3.19-3.29(m，3H)2.78-2.88(m，2H)2.06(s，1H)1.84(d，J＝6.57Hz，3H)1.63(d，J＝14.40Hz，2H)1.26-1.37(m，2H)；LCMS：464[M+1]；c-MetKi：0.056μM。

Embodiment 82: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2-piperazine-1-base-ethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 4-[2-(4-bromo-pyrazol-1-yl)-ethyl]-piperazine-1-carboxylic acid uncle-butyl ester (utilizing general procedure 11 to process) and 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 15; 4; 5,5-tetramethyl--[1,3; 2] dioxane pentaborane-2-yl)-and pyridine-2-base amine, then removal is protected (general procedure 3) and is processed. ¹HNMR(400MHz，DMSO-D6)δppm9.39(s，1H)8.09(s，1H)7.79(s，1H)7.70(s，1H)7.61(dd，J＝8.97，4.93Hz，1H)7.49(t，J＝8.59Hz，1H)7.13(s，1H)6.27(q，J＝6.48Hz，1H)4.47(s，2H)3.27(s，6H)3.11(s，3H)1.85(d，J＝6.82Hz，3H)；LCMS：479[M+1]；c-MetKi：0.047μM。

Embodiment 83: 2-(4-{6-amino-5-[1-(2,6--two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-ethanol

Title compound uses 2-(4-bromo-pyrazol-1-yl)-ethanol (service routine 26 is processed) and 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 15; 4,5,5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes. ¹HNMR(400MHz，DMSO-D6)δppm7.96(s，1H)7.72(s，1H)7.56-7.63(m，2H)7.43-7.52(m，2H)7.07(d，J＝1.52Hz，1H)6.24(q，J＝6.57Hz，1H)4.08-4.17(m，2H)3.70(dt，J＝8.78，5.46Hz，3H)1.84(d，J＝6.57Hz，3H)；LCMS：411[M+1]；c-MetKi：0.046μM。

Embodiment 84: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-[1,3] dioxolane-4-ylmethyl-1H-pyrazoles-4-yl)-pyridine-2-base amine

Title compound is according to program 15, and dioxolane-[1-(2 with 3-for 4-ylmethyl-1H-pyrazoles (utilizing general procedure 11 to process) to use 4-bromo-1-[1,3]; 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4; 4,5,5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes. ¹HNMR(400MHz，DMSO-D6)δppm7.99(s，1H)7.71-7.79(m，2H)7.67(d，J＝3.28Hz，1H)7.55-7.64(m，2H)7.49(td，J＝8.65，2.65Hz，2H)7.08(s，1H)6.25(dd，J＝6.95，2.15Hz，1H)4.91(d，J＝4.04Hz，1H)4.80(d，J＝2.53Hz，1H)4.33(d，J＝16.67Hz，1H)4.20-4.29(m，2H)4.06-4.15(m，1H)3.94(dd，J＝8.34，6.82Hz，2H)3.65(ddd，J＝8.21，6.19，6.06Hz，4H)1.85(d，J＝6.57Hz，3H)1.80(d，J＝6.57Hz，1H)；LCMS：453[M+1]；c-MetKi：0.061μM。

Embodiment 85: 1-[4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-the pyrazol-1-yl methyl)-piperidines-1-yl]-2-hydroxyl-ethyl ketone

Title compound is according to program 15; Use 1-[4-(4-bromo-pyrazol-1-yl methyl) piperidines-1-yl]-2-hydroxyl-ethyl ketone (utilizing general procedure 11 to process) and 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4; 5; 5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes. ¹HNMR(400MHz，DMSO-D6)δppm7.94-8.00(m，1H)7.78(d，J＝7.58Hz，1H)7.72(d，J＝1.26Hz，1H)7.64(s，1H)7.60(dd，J＝8.97，4.93Hz，1H)7.45-7.54(m，1H)7.09(s，1H)6.26(q，J＝6.48Hz，1H)4.31(d，J＝12.38Hz，1H)3.97-4.09(m，4H)3.63(s，1H)2.89(t，J＝12.13Hz，1H)2.56(t，J＝12.13Hz，1H)2.03(ddd，J＝11.05，7.39，3.79Hz，1H)1.85(d，J＝6.57Hz，3H)1.48(d，J＝13.14Hz，2H)1.10-1.18(m，1H)0.98-1.10(m，1H)；LCMS：522[M+1]；c-MetKi：0.03μM。

Embodiment 86: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2,2-dimethyl--[1,3] dioxolane-4-ylmethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound is according to program 15, use 4-bromo-1-(2,2-dimethyl--[1; 3] dioxolane-4-ylmethyl)-1H-pyrazoles (utilizing general procedure 11 to process) and 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4; 5; 5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes. ¹HNMR(400MHz，DMSO-D6)δppm7.82(s，1H)7.73(d，J＝1.77Hz，1H)7.56-7.59(m，1H)7.52-7.56(m，1H)7.40-7.47(m，1H)6.85(d，J＝1.77Hz，1H)6.02-6.11(m，1H)5.69(s，2H)4.32-4.39(m，1H)4.13-4.25(m，2H)4.00(ddd，J＝8.34，6.57，1.26Hz，1H)3.72(ddd，J＝8.65，5.49，3.54Hz，1H)1.76-1.84(m，4H)1.28(d，J＝16.67Hz，3H)1.25(s，3H)；LCMS：481[M+1]；c-MetKi：0.062μM。

Embodiment 87: 3-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-propane-1, the 2-glycol

Title compound is processed according to program 21.Make 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(2,2-dimethyl--[1,3] dioxolane-4-ylmethyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine remove protection with TFA and water. ¹HNMR(400MHz，DMSO-D6)δppm7.96(d，J＝3.54Hz，2H)7.76(s，1H)7.64(d，J＝2.78Hz，1H)7.60(dd，J＝8.97，4.93Hz，1H)7.47(t，J＝8.72Hz，1H)7.11(s，1H)6.23-6.31(m，1H)4.22(d，J＝3.79Hz，1H)4.19(d，J＝3.54Hz，1H)3.96(dd，J＝13.64，7.83Hz，2H)3.72-3.82(m，2H)3.26-3.37(m，2H)1.85(d，J＝6.57Hz，3H)；LCMS ：441[M+1]；c-MetKi：0.028μM。

Embodiment 88: 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-tetramethyleneimine-2-carboxylate methyl ester

Title compound uses 4-(4-bromo-pyrazol-1-yl)-tetramethyleneimine-1 according to program 15, and [1-(2 with 3-for 2-dicarboxylicacid uncle 1--butyl ester 2-methyl esters (utilizing general procedure 11 to process); 6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4,4,5; 5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-and pyridine-2-base amine, then removal is protected (general procedure 3) and is processed. ¹HNMR(400MHz，DMSO-D6)δppm8.09-8.15(m，2H)7.74-7.79(m，3H)7.69(s，1H)7.56-7.62(m，2H)7.47(t，J＝8.72Hz，2H)7.06(s，2H)6.18-6.26(m，2H)5.25(s，1H)5.20(s，1H)4.67-4.79(m，2H)3.77-3.84(m，5H)3.74(d，J＝2.78Hz，3H)3.70(s，1H)3.58(s，3H)2.83(s，1H)2.53-2.62(m，3H)2.44(s，1H)1.84(d，J＝6.57Hz，6H)；LCMS：494[M+1]；c-MetKi：0.034μM。

Embodiment 89: 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-[1-(1-methyl-piperidin-4-yl methyl)-1H-pyrazoles-4-yl]-pyridine-2-base amine

Title compound uses 4-(4-bromo-pyrazol-1-yl methyl)-1-methyl-piperidines (utilizing general procedure 11 to process) and 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(4 according to program 15; 4,5,5-tetramethyl--[1; 3,2] dioxane pentaborane-2-yl)-pyridine-2-base amine processes. ¹HNMR(400MHz，DMSO-D6)δppm8.58(s，1H)8.25(s，1H)8.00(s，2H)7.75(s，2H)7.66(s，2H)7.59(dd，J＝9.09，5.05Hz，2H)7.48(t，J＝8.72Hz，2H)7.09(s，2H)6.20-6.31(m，2H)4.05(d，J＝6.82Hz，3H)3.40(d，J＝12.88Hz，1H)3.19-3.29(m，3H)2.78-2.90(m，3H)2.72(d，J＝4.55Hz，1H)2.07(s，1H)1.85(d，J＝6.57Hz，4H)1.59-1.71(m，3H)1.29-1.40(m，2H)；LCMS：478[M+1]；c-MetKi：0.024μM。

Embodiment 90: 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-tetramethyleneimine-2-carboxylic acid methyl acid amides

Title compound is according to program 20, uses 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-tetramethyleneimine-2-carboxylate methyl ester and methylamine to process. ¹HNMR(400MHz，DMSO-D6)δppm8.96(s，1H)8.45(d，J＝4.55Hz，1H)8.11(s，2H)7.72-7.78(m，3H)7.70(s，1H)7.58(dd，J＝8.97，4.93Hz，2H)7.47(td，J＝8.65，1.39Hz，2H)7.05(d，J＝6.06Hz，2H)6.16-6.24(m，2H)5.14-5.22(m，J＝7.58，7.26，7.11，7.11Hz，1H)4.42-4.50(m，1H)4.31(t，J＝8.59Hz，1H)3.76-3.83(m，1H)3.68-3.75(m，2H)3.51-3.63(m，3H)2.86(dt，J＝13.39，7.83Hz，1H)2.67(t，J＝4.42Hz，5H)2.28-2.39(m，2H)1.83(d，J＝6.57Hz，5H)；LCMS：493[M+1]；c-MetKi：0.034μM。

Embodiment 91: 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-tetramethyleneimine-2-carboxylic acid amide

Title compound is according to program 20, uses the amine (2M ammonia) in 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-pyridin-3-yl }-pyrazol-1-yl)-tetramethyleneimine-2-carboxylate methyl ester and the methyl alcohol to process. ¹HNMR(400MHz，DMSO-D6)δppm9.90(s，1H)8.85(s，1H)8.15(s，2H)7.99(s，2H)7.71-7.81(m，6H)7.59(dd，J＝8.97，4.93Hz，2H)7.48(t，J＝8.72Hz，2H)7.26(s，1H)7.13(s，1H)7.09(d，J＝2.27Hz，2H)6.24(q，J＝6.48Hz，2H)5.25(s，1H)4.42-4.51(m，1H)4.32(t，J＝8.46Hz，1H)3.78(s，1H)3.57(s，2H)2.53-2.63(m，1H)2.32-2.41(m，1H)1.84(d，J＝6.57Hz，5H)；LCMS：479[M+1]；c-MetKi：0.044μM。

Embodiment 92: 3-[1-(2,6-two chloro-3-methoxyphenyls) oxyethyl group]-5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-2-amine

Title compound is according to program 24, and system is from 3-[1-(2,6-two chloro-3-fluoro-phenyl)-oxyethyl group]-5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridine-2-base amine.Raw material can be according to the u.s. patent application serial number of submitting on February 26th, 2,004 10/786; 610; Its title is the example I-615 of " as the aminoheteroaryl compounds of kinases inhibitor "; And on February 26th, 2004 same title submitted to corresponding International Application PCT/US2004/005495 and obtain, it is for reference that its disclosure is all incorporated this paper into it in full. ¹HNMR(400MHz，DMSO-D6)δppm1.77(d，J＝6.57Hz，3H)3.80(s，3H)3.81-3.85(m，3H)5.60(s，2H)6.08(q，J＝6.57Hz，1H)6.86(d，J＝1.52Hz，1H)7.10(d，J＝9.09Hz，1H)7.43(d，J＝8.84Hz，1H)7.47(s，1H)7.69(d，J＝1.77Hz，1H)7.79(s，1H)；LCMS：394[M+1]；c-MetKi：0.012μM。

Embodiment 93: [1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-[(3, the 5-dimethyl-is different for 5-{1-for 3-

Azoles-4-yl) methyl]-1H-pyrazoles-4-yl } pyridine-2-amine

Title compound is according to program 21; Use 4-(chloromethyl)-3,5-dimethyl-different

azoles is processed as alkylating agent. ¹HNMR (400MHz, δ ppm1.85 (d, J=6.57Hz, 3H) 2.20 (s, 3H) 2.43 (s of chloroform-D); 3H) 5.03-5.05 (m, 2H) 6.04 (q, J=6.57Hz, 1H) 6.79 (d; J=1.77Hz, 1H) 6.97-7.13 (m, 1H) 7.29 (q, J=2.86Hz; 2H) 7.57 (s, and 1H) 7.73 (d, J=1.77Hz, 1H); LCMS:477 [M+1]; C-MetKi:0.069 μ M.

Embodiment 94: 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) piperidines-1-carboxylic acid uncle-butyl ester

Title compound uses 4-methanesulfonic root-1-piperidine carboxylic acid uncle-butyl ester (program 11) to process as alkylating agent according to program 21. ¹HNMR (400MHz, δ ppm1.47 (s, 9H) 1.85 (d, J=6.82Hz, 3H) 1.87-1.98 (m, 2H) 2.05-2.20 (m of chloroform-D); 2H) 2.82-2.92 (m, 2H) 4.14-4.34 (m, 3H) 4.75 (s, 2H) 6.06 (q, J=6.82Hz, 1H) 6.86 (d; J=1.52Hz, 1H) 7.00-7.08 (m, 1H) 7.29 (dd, J=8.84,4.80Hz; 1H) 7.47 (s, 1H) 7.56 (s, and 1H) 7.75 (d, J=1.77Hz, 1H); LCMS:551 [M+1]; C-MetKi:0.035 μ M.

Embodiment 95: 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) piperidines-1-carboxylic acid 2-hydroxyl ethyl ester

Title compound uses ethylene carbonate to process as acylating agent according to program 21 and 22. ¹HNMR(400MHz，DMSO-D6)δppm1.79(d，J＝6.57Hz，3H)1.82(d，J＝4.04Hz，2H)1.92-2.08(m，2H)2.96(S，1H)3.97-4.04(m，2H)4.09(d，J＝13.39Hz，2H)4.27-4.40(m，1H)4.78(t，J＝5.56Hz，1H)5.64(s，2H)6.07(q，J＝6.74Hz，1H)6.89(d，J＝1.77Hz，1H)7.43(t，J＝8.72Hz，1H)7.52(s，1H)7.56(dd，J＝8.97，4.93Hz，1H)7.74(d，J＝1.77Hz，1H)7.97(s，1H)；LCMS：539[M+1]；c-MetKi：0.01μM。

Embodiment 96: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(1H-pyrazoles-4-yl) pyridine-2-amine

Title compound is processed according to program 21. ¹HNMR (400MHz, δ ppm 1.60 (s, 1H) 1.84 (d, J=6.57Hz, 3H) 5.07 (s of chloroform-d); 2H) 6.06 (q, J=6.57Hz, 1H) 6.89 (d, J=1.77Hz, 1H) 6.96-7.06 (m; 1H) 7.22-7.33 (m, 1H) 7.67 (s, 2H) 7.80 (d, J=1.52Hz, 1H); LCMS:368 [M+1]; C-MetKi:0.035 μ M.

Embodiment 97: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-[1-(1-sec.-propyl azetidine-3-yl)-1H-pyrazoles-4-yl] pyridine-2-amine

Title compound uses 2-iodopropane to process as alkylating agent according to program 2. ¹HNMR(400MHz，DMSO-D6)δppm?0.88(d，J＝6.06Hz，6H)1.79(d，J＝6.82Hz，3H)2.35-2.42(m，1H)3.28(t，2H)3.62(t，J＝7.58Hz，2H)4.78-4.91(m，1H)5.67(s，2H)6.08(q，J＝6.57Hz，1H)7.43(t，J＝8.72Hz，1H)7.55(dd，J＝8.97，4.93Hz，1H)7.58(s，1H)7.75(d，J＝1.77Hz，1H)8.03(s，1H)；LCMS：465[M+1]；c-MetKi：0.03μM。

Embodiment 98: 2-[4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) piperidines-1-yl] ethanamide

Title compound uses the 2-bromoacetamide to process as alkylating agent according to program 21 and 22. ¹HNMR(400MHz，DMSO-D6)δppm?1.79(d，J＝6.57Hz，3H)1.92-2.08(m，4H)2.16-2.31(m，2H)2.83-2.88(m，2H)2.89(s，2H)4.04-4.17(m，1H)5.64(s，2H)6.07(q，J＝6.74Hz，1H)6.88(d，J＝1.52Hz，1H)7.08-7.16(m，1H)7.20(s，1H)7.43(t，J＝8.72Hz，1H)7.52(s，1H)7.57(dd，J＝8.97，4.93Hz，1H)7.74(d，J＝1.77Hz，1H)7.93(s，1H)；LCMS：508[M+1]；c-MetKi：0.007μM。

Embodiment 99: 5-[1-(the 8-azabicyclo is [3.2.1] oct-3-yl also)-1H-pyrazoles-4-yl]-3-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group] pyridine-2-amine

Title compound is according to program 21, and use 3-methanesulfonyloxy group-8-aza-bicyclo also [3.2.1] octane-8-carboxylic acid uncle-butyl ester is processed as alkylating agent.Raw material obtains through following steps: with NaBH ₄/ ethanol makes also [3.2.1] octane-8-carboxylic acid uncle-butyl ester (the commercially available Fluka of the deriving from) reduction and obtain also [3.2.1] octane-8-carboxylic acid uncle-butyl ester of 3-hydroxyl-8-azabicyclo of 3-oxo-8-azabicyclo, processes corresponding methanesulfonyloxy group compound from it. ¹HNMR(400MHz，MeOD)δppm1.85(d，J＝6.57Hz，3H)1.87-2.11(m，7H)3.69-3.78(m，2H)4.08(d，J＝7.07Hz，1H)4.51-4.67(m，1H)6.14(q，J＝6.57Hz，1H)6.90(s，1H)7.20(t，J＝8.59Hz，1H)7.43(dd，J＝8.97，4.93Hz，1H)7.51(s，1H)7.65(s，1H)7.79(s，1H)；LCMS：477[M+1]；c-MetKi：0.005μM。

Embodiment 100: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-[1-(2H-tetrazolium-5-ylmethyl)-1H-pyrazoles-4-yl] pyridine-2-amine

Title compound uses 5-chloromethyl-1 (2)-tetrazolium to process as alkylating agent according to program 21. ¹HNMR(400MHz，DMSO-D6)δppm 1.84(d，J＝6.57Hz，3H)5.74(s，2H)6.25(q，J＝6.48Hz，1H)7.10(d，J＝1.01Hz，1H)7.47(t，J＝8.72Hz，1H)7.53-7.63(m，1H)7.71(s，1H)7.76(d，J＝1.01Hz，1H)8.14(s，1H)；LCMS：450[M+1]；c-MetKi：0.04μM。

Embodiment 101: 4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) piperidines-1-carboxylic acid, ethyl ester

Title compound uses Vinyl chloroformate to process as acylating agent according to program 21 and 22. ¹HNMR(400MHz，DMSO-D6)δppm1.19(t，J＝7.07Hz，3H)1.71-1.79(m，2H)1.82(d，J＝6.57Hz，3H)1.97-2.06(m，2H)2.93-3.04(m，2H)4.05(q，J＝7.07Hz，4H)4.29-4.47(m，1H)6.17(q，J＝6.32Hz，1H)6.50-6.88(m，2H)7.00(s，1H)7.46(t，J＝8.72Hz，1H)7.58(q，J＝4.55Hz，1H)7.58(s，1H)7.72(d，J＝1.52Hz，1H)8.04(s，1H)；LCMS：523[M+1]；c-MetKi：0.019μM。

Embodiment 102: 2-[3-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) azetidine-1-yl] ethanol

Title compound uses methyl bromoacetate as alkylating agent according to program 2, uses LiBH then ₄As reductive agent, so that methyl esters is reduced into alcohol and processes. ¹HNMR(400MHz，DMSO-D6)δppm1.83(d，J＝6.57Hz，3H)3.02(t，J＝5.81Hz，2H)3.75(q，J＝5.73Hz，2H)3.88-3.99(m，2H)4.18-4.28(m，2H)4.78(t，J＝5.18Hz，1H)5.31-5.42(m，J＝7.96，7.96Hz，1H)6.19(q，J＝6.57Hz，1H)7.01(d，J＝1.26Hz，1H)7.43-7.51(m，1H)7.59(dd，J＝8.97，4.93Hz，1H)7.76(d，J＝1.26Hz，1H)7.78(s，1H)8.15(s，1H)；LCMS：467[M+1]；c-MetKi：0.05μM。

Embodiment 103: 3-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group]-5-{1-[1-(2-methoxy ethyl) azetidine-3-yl]-1H-pyrazoles-4-yl } pyridine-2-amine

Title compound uses the 2-bromo-ethyl-methyl ether to process as alkylating agent according to program 2. ¹HNMR(400MHz，DMSO-D6)δppm?1.79(d，J＝6.57Hz，3H)2.60-2.67(m，2H)3.10-3.18(m，2H)3.22(s，3H)3.35-3.42(m，2H)3.68(t，J＝7.45Hz，2H)4.85-4.97(m，1H)5.67(s，2H)6.08(q，J＝6.40Hz，1H)6.89(d，J＝1.52Hz，1H)7.43(t，J＝8.72Hz，1H)7.56(dd，J＝8.97，4.93Hz，1H)7.58(s，1H)7.75(d，J＝1.52Hz，1H)8.03(s，1H)；LCMS：481[M+1]；c-MetKi：0.07μM。

Embodiment 104: 3-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group]-5-{1-[1-(methylsulfonyl) azetidine-3-yl]-1H-pyrazoles-4-yl } pyridine-2-amine

Title compound is processed according to program 2.Last alkylation program is through making 2-11(1 molar equivalent) is dissolved among the DMF (3 milliliters) and carries out.Add SULPHURYL CHLORIDE (1 molar equivalent) and triethylamine (3 molar equivalent), and will react under the room temperature and stir 16 hours.Then according to general post-treatment condition (program 2), and title compound, 30% yield. ¹HNMR (400MHz, δ ppm 1.85 (d, J=6.82Hz, 3H) 3.03 (s, 3H) 4.35-4.45 (m, 4H) 4.83 (s of chloroform-D); 2H) 5.06 (ddd, J=14.02,7.83,6.44Hz, 1H) 6.06 (q, J=6.82Hz; 1H) 6.84 (d, J=1.77Hz, 1H) 7.02-7.08 (m, 1H) 7.31 (dd, J=8.84,4.80Hz; 1H) 7.53 (s, 1H) 7.64 (s, and 1H) 7.74 (d, J=1.77Hz, 1H); LCMS:499.85 [M+1]; C-MetKi:0.036 μ M.

Embodiment 105: 2-[3-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) azetidine-1-yl]-2-oxo ethanol

Title compound is processed according to program 2.Last alkylation program is through making 2-11(1 molar equivalent) is dissolved among the DMF (3 milliliters) and carries out.Add 2-chloro-2-oxo ETHYLE ACETATE (1 molar equivalent) and triethylamine (5 molar equivalent), and will react under the room temperature and stir 16 hours.Then according to general post-treatment condition (program 2), and 2-[3-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-1H-pyrazol-1-yl) azetidine-1-yl]-2-oxo ETHYLE ACETATE, 27% yield.Make compound be dissolved in MeOH/H ₂Among the O (4:1), then add Pottasium Hydroxide (1 molar equivalent).After at room temperature stirring 3 hours, add H ₂O and EtOAc, and extracted organic phase, dry (Na ₂SO ₄), concentrate, then through the preparation HPLC purifying, and get title compound, 68% yield. ¹HNMR(400MHz，DMSO-D6)δppm1.84(d，J＝6.57Hz，3H)3.95(s，2H)4.08-4.18(m，1H)4.32-4.44(m，2H)4.64(t，J＝8.72Hz，1H)5.24-5.32(m，1H)6.23(q，J＝6.57Hz，1H)7.11(s，1H)7.47(t，J＝8.72Hz，1H)7.59(dd，J＝9.09，5.05Hz，1H)7.74-7.77(m，2H)8.17(s，1H)；LCMS：479.90[M+1]；c-MetKi：0.022μM。

Embodiment 106: 5-{1-[(1-ethanoyl azetidine-3-yl) methyl]-1H-pyrazoles-4-yl }-3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridine-2-amine

Title compound is processed according to program 1.Last alkylation program is through making 1-10(1 molar equivalent) is dissolved in the methylene dichloride (3 milliliters) and carries out.Add diacetyl oxide (1.1 molar equivalent) and triethylamine (3 molar equivalent), and will react under the room temperature and stir 16 hours.Reaction is concentrated, and through hurried chromatography purification (50%EtOAc/ hexane-100%EtOAc gradient), and get title compound, 89% yield. ¹HNMR(400MHz，DMSO-D6)δppm1.71(d，J＝2.78Hz，3H)1.79(d，J＝6.57Hz，3H)2.92-3.03(m，1H)3.62(dd，J＝9.60，5.56Hz，1H)3.82-3.93(m，2H)4.13(t，J＝8.46Hz，1H)4.30(d，J＝7.33Hz，2H)5.67(s，2H)6.07(q，J＝6.57Hz，1H)6.86(s，1H)7.43(t，J＝8.72Hz，1H)7.53-7.58(m，2H)7.73(d，J＝1.77Hz，1H)7.90(d，J＝1.77Hz，1H)；LCMS：477.90[M+1]；c-MetKi：0.029μM。

Embodiment 107: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(1-{ [1-(methylsulfonyl) azetidine-3-yl] methyl }-1H-pyrazoles-4-yl) pyridine-2-amine

Title compound is processed according to program 1.Last alkylation program is through making 1-10(1 molar equivalent) is dissolved among the DMF (3 milliliters) and carries out.Add SULPHURYL CHLORIDE (1 molar equivalent) and triethylamine (3 molar equivalent), and will react under the room temperature and stir 16 hours.Then according to general post-treatment condition (program 1), and title compound, 54% yield. ¹HNMR(400MHz，DMSO-D6)δppm?1.85(d，J＝6.57Hz，3H)2.99(s，3H)3.01-3.12(m，1H)3.77(dd，J＝8.08，6.06Hz，2H)3.97(t，J＝8.34Hz，2H)4.37(d，J＝7.07Hz，2H)5.74(s，2H)6.14(q，J＝6.40Hz，1H)6.94(d，J＝1.52Hz，1H)7.50(t，J＝8.72Hz，1H)7.58-7.65(m，2H)7.79(d，J＝1.77Hz，1H)8.01(s，1H)；LCMS：514.10[M+1]；c-MetKi：0.044μM。

Embodiment 108: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-{1-[(1-sec.-propyl azetidine-3-yl) methyl]-1H-pyrazoles-4-yl } pyridine-2-amine

Title compound is processed according to program 1.Last alkylation program is through making 1-10(1 molar equivalent) is dissolved among the DMF (3 milliliters) and carries out.Add 2-iodopropane (1 molar equivalent) and triethylamine (3 molar equivalent), and stir 16 hours under will reacting on 50 ℃.Then according to general post-treatment condition (program 1), and title compound, 15% yield. ¹HNMR(400MHz，DMSO-D6)δppm0.80(d，J＝6.06Hz，6H)1.79(d，J＝6.32Hz，3H)2.18(ddd，J＝12.25，6.32，6.19Hz，1H)2.65(td，J＝13.45，6.19Hz，1H)2.83(t，J＝5.31Hz，2H)3.13(t，J＝6.69Hz，2H)4.22(d，J＝7.33Hz，2H)5.65(s，2H)6.07(q，J＝6.65Hz，1H)6.86(d，J＝1.52Hz，1H)7.43(t，J＝8.72Hz，1H)7.51(s，1H)7.55(dd，J＝8.97，4.93Hz，1H)7.72(d，J＝1.52Hz，1H)7.85(s，1H)；LCMS：478.20[M+1]；c-MetKi：0.057μM。

Embodiment 109: 2-[3-(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) azetidine-1-yl] ethanamide

Title compound is processed according to program 2.Last alkylation program is through making 2-11(1 molar equivalent) is dissolved among the DMF (3 milliliters) and carries out.Add 2-iodopropane (1 molar equivalent) and triethylamine (5 molar equivalent), and will react under the room temperature and stir 16 hours.Then according to general post-treatment condition (program 2), and title compound, 23% yield. ¹HNMR(400MHz，DMSO-D6)δppm1.79(d，J＝6.82Hz，3H)3.09(s，2H)3.42-3.51(m，2H)3.78(t，J＝7.58Hz，2H)4.95(qd，J＝6.86，6.69Hz，1H)5.67(s，2H)6.08(q，J＝6.65Hz，1H)6.90(d，J＝1.52Hz，1H)7.08(s，1H)7.19(s，1H)7.43(t，J＝8.72Hz，1H)7.54-7.59(m，2H)7.76(d，J＝1.77Hz，1H)8.11(s，1H)；LCMS：478.90[M+1]；c-MetKi：0.021μM。

Embodiment 110: 5-[1-(1-ethanoyl azetidine-3-yl)-1H-pyrazoles-4-yl]-3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridine-2-amine

Title compound is processed according to program 2.Last alkylation program is through making 2-11(1 molar equivalent) is dissolved among the DMF (3 milliliters) and carries out.Add diacetyl oxide (1 molar equivalent) and triethylamine (3 molar equivalent), and will react under the room temperature and stir 16 hours.Then according to general post-treatment condition (program 2), and title compound, 9% yield. ¹HNMR(400MHz，DMSO-D6)δppm1.79(d，J＝6.57Hz，3H)1.80(s，3H)4.08(dt，J＝9.35，4.67Hz，1H)4.27(t，J＝9.09Hz，1H)4.36(ddd，J＝8.97，4.42，4.29Hz，1H)4.54(t，J＝8.46Hz，1H)5.20(ddd，J＝13.26，7.96，5.31Hz，1H)5.69(s，2H)6.08(q，J＝6.57Hz，1H)6.91(d，J＝1.77Hz，1H)7.44(t，J＝8.72Hz，1H)7.56(dd，J＝9.09，5.05Hz，1H)7.66(s，1H)7.76(d，J＝1.77Hz，1H)8.07(s，1H)；LCMS：464.10[M+1]；c-MetKi：0.032μM。

Embodiment 111: 3-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl] azetidine-1-yl } acetonitrile

Title compound is processed according to program 1.Last alkylation program is through making 1-10(1 molar equivalent) is dissolved in the methylene dichloride (3 milliliters) and carries out.Add bromoacetonitrile (1 molar equivalent) and triethylamine (3 molar equivalent), and will react under the room temperature and stir 16 hours.Then according to general post-treatment condition (program 1), and title compound, 51% yield. ¹HNMR(400MHz，DMSO-D6)δppm1.79(d，J＝6.57Hz，3H)2.80(ddd，J＝13.14，7.33，5.81Hz，1H)3.08(t，J＝6.44Hz，2H)3.32(t，J＝7.20Hz，2H)3.59(s，2H)4.25(d，J＝7.33Hz，2H)5.66(s，2H)6.07(q，J＝6.57Hz，1H)6.86(d，J＝1.77Hz，1H)7.43(t，J＝8.72Hz，1H)7.52(s，1H)7.56(dd，J＝8.97，4.93Hz，1H)7.72(d，J＝1.52Hz，1H)7.88(s，1H)；LCMS：475.10[M+1]；c-MetKi：0.037μM。

Embodiment 112: 5-(1-{ [1-(cyclopropyl methyl) azetidine-3-yl] methyl }-1H-pyrazoles-4-yl)-3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridine-2-amine

Title compound is processed according to program 1.Last alkylation program is through making 1-10(1 molar equivalent) is dissolved among the DMF (3 milliliters) and carries out.Add bromine Trimetylene (1 molar equivalent) and triethylamine (3 molar equivalent), and will react under the room temperature and stir 16 hours.Then according to general post-treatment condition (program 1), and title compound, 36% yield. ¹HNMR(400MHz，DMSO-D6)δppm0.03(q，J＝4.80Hz，2H)0.34(ddd，J＝8.08，5.68，4.17Hz，2H)0.62-0.72(m，1H)1.79(d，J＝6.82Hz，3H)2.18(d，J＝6.57Hz，2H)2.69-2.78(m，1H)2.90(t，J＝5.81Hz，2H)3.19(t，J＝7.20Hz，2H)4.23(d，J＝7.33Hz，2H)5.65(s，2H)6.07(q，J＝6.57Hz，1H)6.86(d，J＝1.52Hz，1H)7.43(t，J＝8.72Hz，1H)7.51(s，1H)7.55(dd，J＝8.97，4.93Hz，1H)7.72(d，J＝1.77Hz，1H)7.86(s，1H)；LCMS：490.10[M+1]；c-MetKi：0.047μM。

Embodiment 113: 2-{3-[(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) methyl] azetidine-1-yl } ethanamide

Title compound is processed according to program 1. ¹HNMR(400MHz，DMSO-D6)δppm1.79(d，J＝6.82Hz，3H)2.69-2.80(m，1H)2.91(s，2H)3.02(t，J＝5.68Hz，2H)3.29(td，J＝7.07，2.53Hz，2H)4.28(d，J＝7.33Hz，2H)5.66(s，2H)6.07(q，J＝6.74Hz，1H)6.85(d，J＝1.77Hz，1H)7.06(d，J＝19.45Hz，2H)7.43(t，J＝8.72Hz，1H)7.52(S，1H)7.56(dd，J＝8.97，4.93Hz，1H)7.72(d，J＝1.77Hz，1H)7.85(s，1H)；LCMS：493[M+1]；c-MetKi：0.035μM。

Embodiment 114: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-[1-({ 1-[(dimethylamino) ethanoyl] azetidine-3-yl } methyl)-1H-pyrazoles-4-yl] pyridine-2-amine

Title compound is processed according to program 1. ¹HNMR(400MHz，DMSO-D6)δppm1.79(d，J＝6.57Hz，3H)2.13(d，J＝2.02Hz，6H)2.85(d，J＝2.78Hz，2H)2.95-3.05(m，1H)3.67(dd，J＝9.60，5.31Hz，1H)3.89(t，J＝8.97Hz，1H)3.96(dd，J＝9.09，5.31Hz，1H)4.19(t，J＝8.59Hz，1H)4.29(d，J＝7.07Hz，2H)5.67(s，2H)6.07(q，J＝6.57Hz，1H)6.86(s，1H)7.43(t，J＝8.72Hz，1H)7.49-7.59(m，2H)7.73(d，J＝1.52Hz，1H)7.90(d，J＝2.02Hz，1H)；LCMS：521.10[M+1]。

Embodiment 115: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-[1-(8-methyl-8-azabicyclo is [3.2.1] oct-3-yl also)-1H-pyrazoles-4-yl] pyridine-2-amine

Title compound is processed according to program 21 and 22. ¹HNMR(400MHz，MeOD)δppm1.72-1.84(m，2H)1.86(d，J＝6.82Hz，3H)1.90-2.02(m，2H)2.08-2.25(m，4H)2.38(s，3H)3.32-3.40(m，2H)4.43-4.60(m，1H)6.17(q，J＝6.57Hz，1H)6.92(d，J＝1.77Hz，1H)7.11-7.29(m，1H)7.45(dd，J＝8.84，4.80Hz，1H)7.50(s，1H)7.78(s，1H)；LCMS：491[M+1]；c-MetKi：0.009μM。

Embodiment 116: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-[1-(1,1-two bridging oxygens tetrahydrochysene-2H-thiapyran-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine

Title compound is processed according to program 21. ¹HNMR(400MHz，MeOD)δppm?1.94(d，J＝6.57Hz，3H)2.44(d，J＝13.90Hz，2H)2.53-2.70(m，2H)4.53-4.66(m，1H)4.89-4.95(m，2H)6.35(q，J＝6.15Hz，1H)7.15(s，1H)7.28(t，J＝8.59Hz，1H)7.50(dd，J＝8.59，4.55Hz，1H)7.60(s，1H)7.65(s，1H)7.95(s，1H)；LCMS：500[M+1]；c-MetKi：0.017μM。

Embodiment 117: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-[1-(1,1-two bridging oxygens tetrahydrochysene-2H-thiapyran-3-yl)-1H-pyrazoles-4-yl] pyridine-2-amine

Title compound is processed according to program 21. ¹HNMR(400MHz，MeOD)δppm1.94(d，J＝6.57Hz，3H)2.03-2.13(m，2H)2.18-2.32(m，2H)3.07-3.21(m，2H)3.42-3.50(m，1H)3.61(t，J＝12.76Hz，1H)4.73-4.82(m，1H)6.35(q，J＝6.57Hz，1H)7.15(s，1H)7.28(t，J＝8.59Hz，1H)7.51(dd，J＝8.97，4.93Hz，1H)7.59(s，2H)7.66(s，2H)7.96(s，2H)；LCMS：500[M+1]；c-MetKi：0.014μM。

Embodiment 118: 3-[1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(1-piperidin-4-yl-1H-pyrazoles-4-yl) pyridine-2-amine

Title compound is processed according to program 23. ¹HNMR(400MHz，DMSO-D6)δppm1.65-1.76(m，2H)1.79(d，J＝6.57Hz，3H)1.85-1.95(m，2H)2.51-2.64(m，2H)3.01(d，J＝12.38Hz，2H)4.03-4.23(m，1H)5.63(s，2H)6.07(q，J＝6.57Hz，1H)6.88(d，J＝1.52Hz，1H)7.43(t，J＝8.72Hz，1H)7.51(s，1H)7.56(dd，J＝8.97，4.93Hz，1H)7.74(d，J＝1.77Hz，1H)7.90(s，1H)；LCMS：451[M+1]。

Embodiment 119: [4-(4-{6-amino-5-[1-(2,6-two chloro-3-fluoro-phenyl) oxyethyl group] pyridin-3-yl }-the 1H-pyrazol-1-yl) piperidines-1-yl] methyl acetate

Title compound is processed according to program 23. ¹HNMR (400MHz, δ ppm1.83 (d, J=6.57Hz, 3H) 2.01-2.21 (m, 4H) 2.32-2.49 (m, 2H) 3.05 (d of chloroform-d); J=11.87Hz, 2H) 3.28 (s, 2H) 3.72 (s, 3H) 3.98-4.23 (m, 1H) 4.76 (s, 2H) 6.05 (q; J=6.82Hz, 1H) 6.84 (d, J=1.77Hz, 1H) 6.96-7.09 (m, 1H) 7.29 (dd, J=8.84; 4.80Hz, 1H) 7.47 (s, 1H) 7.54 (s, and 1H) 7.74 (d, J=1.77Hz, 3H); LCMS:523 [M+1].

Biology embodiment

Will be understood that and in the compound of any particular series, will observe a series of BAs.Its at present preferred aspect, the present invention relates to can modulation, the compounds of adjusting and/or arrestin kinase activity.Can adopt following detection to be wanted active compound to select the confirmation optimum extent.

Trace routine

Following in vitro the detection can be used for measuring different compound of the present invention to the activity of one or more PK and the level of effect.Can use technology well known in the art, seemingly detect along same routes design class about any PK.Bibliographic reference (Technikova-Dobrova Z, Sardanelli AM, Papa S FEBS Lett.1991 Nov4 are provided; 292:69-72).

General procedure is following: compound and kinase assay reagent are introduced in the test holes.Detection causes through adding kinases.Enzyme inhibitors reduces measured enzymic activity.

In the coupling spectrophotometry detected continuously, ADP was through kinase whose time-dependent manner production, and the wear rate of analyzing NADH through the reduction of measuring 340 millimicrons of following optical densitys records.When PK produced ADP, it was changed into ATP again through reacting with phosphoenolpyruvic acid and pyruvate kinase.In this reaction, also produce pyruvic acid.Pyruvic acid is then through being converted to lactic acid with the lactic dehydrogenase enzyme reaction, and it makes NADH change into NAD simultaneously.NADH has under 340 millimicrons can measure optical density, yet NAD does not have.

Hereinafter provides about specific PK being carried out the present preferred version of continuous coupling spectrophotometry experiment.But the modification of this scheme is used to measure the activity of compound to other RTK and CTK and STK, well in those skilled in the art's the ken.

The continuous coupling spectrophotometry of HGFR detects

These check and analysis HGFR is to the tyrosine kinase activity of the low thing peptide of Met-2, and this peptide is a kind of peptide derived from HGFR activation ring.

Material and reagent:

1. derive from HGFR enzyme (Met, active) the catalogue #14-526 of Upstate

2.Met-2 peptide (HGFR activation ring) Ac-ARDMYDKEYYSVHNK (MW=1960).Be dissolved in 200mM HEPES, among the pH7.5,10mM storing solution form.

3.1M PEP (phosphoenolpyruvic acid) in 200mM HEPES, pH7.5

4.100mM NADH (B-VITAMIN PP adenine dinucleotide, reduction form) in 200mM HEPES, pH7.5

5.4M MgCl ₂(magnesium chloride) is at ddH ₂Among the O

6.1M DTT (disulfide group threitol) in 200mM HEPES, pH7.5

7.15 units per ml LDH (serum lactic dehydrogenase)

8.15 units per ml PK (pyruvate kinase)

9. be dissolved in ddH ₂5M NaCl among the O

10. tween 20 (albumen quality and grade) 10% solution

11.1M HEPES damping fluid: (N-[2-hydrogen ethyl] piperazine-N-[2 ethane sulfonic aicd]) sodium salt.Be dissolved in ddH ₂Among the O, adjustment pH to 7.5 makes volume reach 1 liter.Filter with 0.1 micron filter.

12.HPLC level water; Burdick and Jackson#365-4,1x4 liter (or suitable)

13.100％DMSO(Sigma)

14.Costar#3880-flat half area plate of black transparent is used for K _iMeasure with % and suppress

15.Costar#3359-96 the hole polypropylene board, rounded bottom is used for serial dilution

16.Costar#3635-UV-plate, transparent flat underside is used for % and suppresses

17.Beckman DU-650w/ minicell retainer

18.Beckman 4-position minicell cup

Program:

Preparation is used for the dilution buffer liquid (DB) (for 30 ml of formulation) of enzyme

1.DB final concn is 2mM DTT, 25mM NaCl ₂, 5mM MgCl ₂, 0.01% tween 20 and 50mM HEPES damping fluid, pH7.5.

2. through adding HEPES to 28.1 milliliter of ddH of 1.5 milliliters of 1M ₂Among the O, constitute 50mMHEPES.Add all the other reagent.In 50 milliliters of conical bottles, add 60 microlitre 1MDTT, 150 microlitre 5M NaCl ₂, 150 microlitre 1M MgCl ₂And 30 microlitres, 10% tween 20, and get 30 milliliters of TVs.

3. vortex 5-10 second.

4. take out DB liquid part with 1 milliliter/pipe equal portions, and pipe is labeled as " DBHGFR "

5. note: this can prepare in advance and store.

With untapped aliquot sample in micro-centrifuge tube, freezing in-20 ℃ of refrigerators.

The preparation compound

1. for the diluted chemical compound plate, add in the 1st row of 4 microlitre 10mM storing solution to plates, and make volume reach 100 microlitres with 100%DMSO.

2. set up precision (Precision) 2000 dilution methods.Final concn is that 200 μ M compounds are at 50%DMSO, among the 100mM HEPES (serial dilution in 1: 2).

Preparation coupling enzyme buffer liquid:

1. the final concn in detecting:

Final concn during reagent (storing solution concentration) detects

a.PEP(1M) 1mM

b.NADH(100mM) 300μM

c.MgCl ₂(4M) 20mM

d.DTT(1M) 2mM

e.ATP(500mM) 300μM

f.HEPES?200mM(pH7.5) 100mM

G. pyruvate kinase (PK) 15 units per ml

H. serum lactic dehydrogenase (LDH) 15 units per ml

I.Met-2 peptide (10mM) 0.500mM

j.HGFR 50nM

2. about 10 milliliters of reaction buffers, with 10 microlitre 1M PEP, 33 microlitre 100mMNADH, 50 microlitre 4M MgCl ₂, 20 microlitre 1M DTT, 6 microlitre 500mM ATP and 500 microlitre 10mM Met-2 peptides are added in the 100mM HEPES pH of buffer 7.5, and vortex/mixing.

3. add coupling enzyme, LDH and PK to reaction mixture.Mix through the gentleness inversion.

The operation sample

1. spectrophotometer is set:

I. optical density wavelength (λ): 340 millimicrons

Ii. incubation time: 10 minutes

Iii. running time: 10 minutes

Iv. temperature: 37 ℃

2. add in each hole of 85 microlitre CE reaction mixture to check-out consoles.

3. add 5 microlitres in the hole of diluted compounds to check-out console.

4. adding 5 microlitres supplies 50%DMSO that negative control uses to the rank rear of check-out console.

5. mix with hyperchannel pipettor or orbital oscillation device.

6. cultivated 10 minutes in advance down at 37 ℃.

7. add 10 microlitre 500nM HGFR to each hole of check-out console; Last HGFR concentration is 50nM, is in 100 microlitres at total last volume.

λ=340 millimicron with 37 ℃ under, measured active 10 minutes.

Following in vitro the detection can be in order to measure the different compounds of the present invention to the activity of one or more PK and the level of effect.Can use technology well known in the art, along the same routes about any PK, design class is like detecting.

Detection described in several this paper is carried out (people such as Voller, 1980, " enzyme-linked immunosorbent assay " with ELISA (enzyme linked immunological absorption insert measure) form; Clinical immunology handbook (Manual of Clinial Immunology); The 2nd edition, Rose and Friedman, AM.Soc.Of Microbiology, Washington, D.C., 359-371 page or leaf).General procedure is following: with natural way or recombination form the compound introduction is expressed in the kinase whose cell of test, gone through the selected time, then, if the test kinases is an acceptor, then add the part of known meeting activation this receptor.Make cytolysis, and lysate is transferred in the hole of elisa plate, this plate is coated with the specific antibody of the substrate of identification enzyme phosphorylation reaction in advance.The non-substrate composition of cellular lysate is washed off, and discerned the amount of the antibody test of Tyrosine O-phosphate, compare with the control cells that does not contact with testing compound to substrate phosphorylation with specificity property ground.

Hereinafter provide the ELISA experiment of present preferred version carry out to(for) specific PK in.But the modification of these schemes is used to measure the activity of compound to other RTK and CTK and STK, well in those skilled in the art's the ken.

Described in this article other detects the amount of measuring the obtained DNA of the kinase whose activation of response test, and it is the general measure of hyperplasia response.The general procedure of this detection is following: with natural way or with recombination form the compound introducing is expressed in the kinase whose cell of test, gone through the selected time, then, if the test kinases is an acceptor, then add the part of known meeting activation this receptor.After cultivation is spent the night at least, add dna marker reagent, for example 5-bromouracil deoxyribose (BrdU) or H ³-thymidine.The amount of marker DNA is with anti--BrdU antibody, or detects through measuring radioactivity, and with the control cells comparison that contact with test compound.

MET changes phosphorylation assay

This detection is used for measuring to gathering (L-glutamic acid: trorsine 14: 1) the Tyrosine O-phosphate level of substrate, a kind of mode of changeing the agonist/antagonist of phosphorylation as the met that differentiates substrate.

Material and reagent:

1.Corning 96-hole elisa plate, Corning catalogue #25805-96.

2. gather (glu-tyr), 4: 1, the Sigma catalog number; P0275.

3.PBS, Gibco catalogue #450-1300EB

4.50mM?HEPES

5. blocking-up damping fluid: make 25 gram bovine serum albumins, Sigma catalog number A-7888 is dissolved among 500 milliliters of PBS, filters through 4 microns filters.

6. the purifying gst fusion protein matter that contains the Met kinase domain, SUGEN company

7.TBST damping fluid.

8.10% moisture (MilliQue H ₂O) DMSO.

9.10mM moisture (dH ₂O) adenosine-5 '-triphosphoric acid, Sigma catalog number A-5394.

10.2 * kinase dilution damping fluid: for 100 milliliters, with 10 milliliters of 1MHEPES of pH7.5 and 0.4 milliliter of 5%BSA/PBS, 0.2 milliliter of 0.1M Trisodium vanadate and 1 milliliter of 5M sodium-chlor at 88.4 milliliters of dH ₂Mix among the O.

11.4 * ATP reaction mixture: for 10 milliliters, with 0.4 milliliter of 1M manganous chloride and 0.02 milliliter of 0.1M ATP at 9.56 milliliters of dH ₂Mix among the O.

12.4 * negative control mixture: for 10 milliliters, with 0.4 milliliter of 1M manganous chloride at 9.6 milliliters of dH ₂Mix among the O.

13.NUNC 96-hole V-type bottom polypropylene board, the catalogue #S-72092 of Applied Science Fiction Co. (Applied Scientific Catalog)

14.500mM?EDTA。

15. antibody dilution buffer:, 10 milliliters of 5%BSA/PBS, 0.5 milliliter of 5%

instant-dissolved milk powder and 0.1 milliliter of 0.1M Trisodium vanadate in PBS are mixed in 88.4 milliliters of TBST for 100 milliliters.

16. the anti-phosphotyrosine antibody of rabbit polyclonal, SUGEN company

17. the goat antirabbit HRPO is puted together antibody, Biosource company

18.ABTS solution: for 1 liter, with 19.21 gram Hydrocerol As, 35.49 gram Na ₂HPO ₄Reach 500 milligrams of ABTS and capacity dH ₂O mixes, to cause 1 liter.

19.ABTS/H ₂O ₂: using five minutes before, with 15 milliliters of ABST solution and 2 microlitre H ₂O ₂Mix.

20.0.2M?HCl

Program:

1. gather (Glu-Tyr) with 2 micrograms in 100 microlitre PBS and apply elisa plate, keep spending the night down in 4 ℃.

2. with 150 microlitre 5%BSA/PBS, plate resistance was broken 60 minutes.

3. with PBS wash plate twice, then once with 7.4 washings of 50mM Hepes pH of buffer.

4. add the diluted kinases of 50 microlitres to porose (purified kinases dilutes with the kinase dilution damping fluid.Final concn should be 10 nanogram(ng)s/hole).

5. add 25 microlitre test compounds (in 4%DMSO) or supply contrast usefulness independent DMSO (4%, at dH ₂Among the O) to plate.

6. kinases/compound was cultivated 15 minutes.

7. add 25 microlitre 40mM MnCl ₂To negative control wells.

8. add 25 microlitre ATP/MnCl ₂Mixture is to all other holes (except negative control).Cultivated 5 minutes.

9. add 25 microlitre 500mM EDTA with termination reaction.

10. with TBST wash plate 3x.

11. add with 1: 10,000 be diluted in 100 microlitre rabbit polyclonals in the antibody dilution buffer anti--Ptyr is to each hole.Incubated at room temperature is one hour under vibration.

12. with TBST wash plate 3x.

13. with Biosource HRP put together anti--rabbit antibody was with 1: 6,000 is diluted in the antibody dilution buffer.100 microlitres are added in every hole, and under vibration incubated at room temperature one hour.

14. with PBS wash plate 1 *.

15. add 100 microlitre ABTS/H ₂O ₂Solution is to each hole.

16. if necessary, 100 microlitre 0.2M HCl, the development of termination reaction are added in then every hole.

17. on the Dynatech MR7000ELISA reader of the reference screen of test screen with 410nM and 630nM, read plate.

BrdU mixes mensuration

Following mensuration is used through designing to express the cell of selected acceptor, and through measuring BrdU mixing in DNA, the purpose of appraisals compound is to the effect of part inductive DNA composite reactive then.

Following material, reagent and program are general concerning each following BrdU mixes mensuration.Noticed the variation in the particular assay.

General material and reagent:

1. the part that is fit to.

2. the engineering cell that is fit to.

3.BrdU labelled reagent: 10mM, in PBS, pH7.4 (Roche Molecular Biochemicals, Indianapolis, IN).

4.FixDenat: fixed solution (Roche Molecular Biochemicals, Indianapolis, IN).

5. anti--BrdU-POD: the mouse monoclonal antibody of puting together with peroxidase (Chemicon, Temecula, CA).

6.TMB substrate solution: TMB (TMB, available immediately, Roche Molecular Biochemicals, In dianapolis, IN).

7.PBS washing soln: 1 * PBS, pH7.4.

8. BAS (BSA), and the part of V powder (Sigma Chemical Co., USA).

General procedure:

1. at 10%CS, 2mM Gln is inoculated in 96 orifice plates in DMEM cell with 8000 cells/well.Cell is in 37 ℃, 5%CO ₂Middle overnight cultures.

2.24 after hour, cell is washed with PBS, then in the substratum that does not contain serum (0%CS and have the DMEM of 0.1%BSA) through weary 24 hours of serum consumption.

3. in the 3rd day, the part and the test compound that are fit to are added in the cell simultaneously.Negative control hole is accepted not contain serum and is only had the DMEM of 0.1%BSA; Positive control cell is accepted part, but does not have test compound.Test compound has not containing serum among the DMEM of part and is prepared in 96 orifice plates, and the dilution of continuity ground, and 7 kinds of experimental concentration are provided.

4. ligand activation is after 18 hours, add diluted BrdU labelled reagent (1: 100, in DMEM, 0.1%BSA), and cell cultivated 1.5 hours with BrdU (final concn is 10 μ M).

5. after labelled reagent is cultivated, rap inverted plate through decant and on paper handkerchief, to remove substratum.Add FixDenat solution (50 microlitres/hole), and with plate at room temperature, on the plate vibrator, cultivated 45 minutes.

6. rap inverted plate through decant and on paper handkerchief, to remove FixDenat solution.Add breast (5% dehydrated milk among the PBS, 200 microlitres/hole) as blocking solution, and with plate at room temperature, on the plate vibrator, cultivated 30 minutes.

7. remove blocking solution through decant, and with the hole with the PBS washing once.Add anti--BrdU-POD solution (be diluted in PBS at 1: 200, among the 1%BSA, 50 microlitres/hole), and with plate at room temperature, on the plate vibrator, cultivated 90 minutes.

8. through decant and with PBS flushing port 5 times, removing antibody conjugates, and through being inverted and on paper handkerchief, rapping drying plate.

9. add tmb substrate solution (100 microlitres/hole), and at room temperature, on the plate vibrator, cultivated 20 minutes, till the color development is enough to supply photometer to detect.

10. the optical density of sample is measured on Dynatech elisa plate reader (in " dual wavelength " pattern, having the screen that under 490 millimicrons, reads, as a reference wavelength) under 410 millimicrons.

HGF-inductive BrdU mixes mensuration

Material and reagent:

Recombinant human HGF (catalog number 249-HG, R&D Systems company, USA).

2.BxPC-3 cell (ATCC CRL-1687).

All the other materials and reagent are all as above-mentioned.

Program:

With cell with 9000 cells/well, in RPMI 10%FBS, be inoculated in 96 orifice plates.Cell lies in 37 ℃, 5%CO ₂Middle overnight cultures.

2.24 after hour, cell is washed with PBS, did not contain in the substratum (RPMI has 0.1%BSA) of serum the serum consumption weary 24 hours at 100 microlitres then.

3. in the 3rd day, contain part and (, in having the RPMI of 0.1%BSA, process with 1 mcg/ml; Last HGF concentration is 200 millimicro grams per milliliters) be added in the cell with 25 microlitres of test compound.Negative control hole accepts that 25 microlitres do not contain serum and the RPMI that only has 0.1%BSA; Positive control cell is accepted part (HGF) but is not had test compound.Test compound does not have among the RPMI of part not containing serum with 5 times of its final concns, in 96 orifice plates, processes, and the dilution of continuity ground, to obtain 7 kinds of experimental concentration.Typically, the highest final concn of test compound is 100 μ M, and uses 1: 3 extent of dilution (anticipate promptly, final trial compound concentration scope is 0.137-100 μ M).

4., after 18 hours the diluted BrdU labelled reagent of 12.5 microlitres (1: 100 at RPMI, among the 0.1%BSA) is added in each hole in ligand activation, and cell was cultivated 1 hour with BrdU (final concn is 10 μ M).

5. identical with general procedure.

6. identical with general procedure.

7. remove blocking solution through decant, and with the hole with the PBS washing once.Add anti--BrdU-POD solution (being diluted in PBS at 1: 100, among the 1%BSA) (100 microlitres/hole), and with plate at room temperature, on the plate vibrator, cultivated 90 minutes.

8. identical with general procedure.

9. identical with general procedure.

1O. it is identical with general procedure.

Cell HGFR autophosphorylation is measured

(ATCC) is used in this mensuration with the A549 cell.Cell is seeded in 96 orifice plates in growth medium (RPMI+10%FBS), and 37 ℃ of following overnight cultures, for adhering to.Make cellular exposure to hungry substratum (RPMI+0.05%BSA).The diluent of suppressor factor is added into plate, and cultivated 1 hour down at 37 ℃.Then, through adding 40 millimicro grams per milliliter HGF, irritation cell 15 minutes.With cell with the 1mM Na among the HBSS ₃VO ₄Washing is once dissolved then.With lysate with the 1mM Na among the HBSS ₃VO ₄Dilution and is transferred to 96 holes goat anti-rabbit coated board (Pierce), this plate is coated with in advance anti--HGFR antibody (Zymed Laboratories).With plate in 4 ℃ of following overnight cultures, and with 1% polysorbas20 among PBS washing seven times.With HRP-PY20 (Santa Cruz) dilution, and be added into plate, go through cultivation in 30 minutes.Then, plate is washed again, and add TMB peroxidase substrate (Kirkegaard & Perry), and cultivated 10 minutes.Then, through adding 0.09NH ₂SO ₄, reaction is stopped.Plate under the OD-450 millimicron, is used spectrophotometer measurement.IC ₅₀Value uses four parameter analyses to calculate through fitting of a curve.

The HGFR that has measured The compounds of this invention suppresses active; Data presentation is in each embodiment.The Ki data are to use the continuous coupling spectrophotometry of HGFR to detect and obtain, and IC ₅₀Data are to use cell HGFR autophosphorylation measure to obtain, this in two assay method all be described in the preceding text.

Though separate the present invention with reference to specific arguing with embodiment preferred, person of skill in the art will appreciate that, can pass through normal experiment and enforcement of the present invention, carry out modification and correction.Therefore, the present invention also is not intended to be subject to above stated specification, but is defined with literary composition appended claim and equivalents thereof.

All reference of quoting among this paper comprise any priority document, and it is for reference all to incorporate this paper in full into it in view of the above.

Claims

1. formula 1Compound,

Or its pharmacy acceptable salt, in the formula:

Y is N or CR ¹²

A is a phenyl, and it is optional by one or more R ³Group replaces;

R ¹Be selected from

It is optional by one, two or three R ¹³Group replaces;

R ²Be hydrogen;

Each R ³Be halogen, C independently _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12The assorted alicyclic group of aryl, 3-12 unit, 5-12 unit heteroaryl ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-CN ,-C (O) R ⁴,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶Or-NR ⁴S (O) _pR ⁵

Each R ⁴, R ⁵, R ⁶And R ⁷Be hydrogen, halogen, C independently _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl, C _3-12Naphthenic base, C _6-12Aryl, the assorted alicyclic group of 3-12 unit or 5-12 unit heteroaryl;

R ⁹Be methyl and R ¹⁰Be hydrogen;

R ¹²Be hydrogen;

Each R ¹³Be halogen, C independently _1-12Alkyl, C _2-12Thiazolinyl, C _2-12Alkynyl ,-S (O) _mR ⁴,-SO ₂NR ⁴R ⁵,-S (O) ₂OR ⁴,-NO ₂,-NR ⁴R ⁵,-CN ,-OC (O) R ⁴,-O (CR ⁶R ⁷) _nR ⁴,-NR ⁴C (O) R ⁵,-(CR ⁶R ⁷) _nC (O) OR ⁴,-(CR ⁶R ⁷) _nOR ⁴,-(CR ⁶R ⁷) _nC (O) NR ⁴R ⁵,-C (=NR ⁶) NR ⁴R ⁵,-NR ⁴C (O) NR ⁵R ⁶,-NR ⁴S (O) _pR ⁵,-(CR ⁶R ⁷) _n(3-12 unit is assorted alicyclic) ,-(CR ⁶R ⁷) _n(C _3-12Naphthenic base) ,-(CR ⁶R ⁷) _n(C _6-12Aryl) ,-(CR ⁶R ⁷) _n(5-12 unit heteroaryl) or-(CR ⁶R ⁷) _nC (O) R ⁴, the R on the adjacent atom ¹³Group can merge and form C _6-12Aryl, 5-12 unit heteroaryl, C _3-12The assorted alicyclic group of naphthenic base or 3-12 unit, and R ¹³In each hydrogen optional by R ³Replace;

Each m is 0,1 or 2 independently;

Each n is 0,1,2,3 or 4 independently;

T is 1, and

Each p is 1 or 2 independently;

2. the compound of claim 1, wherein Y is N and R ²Be hydrogen.

3. the compound of claim 1, wherein Y is CR ¹², R ²Be hydrogen, and R ¹²Be hydrogen.

4. the compound of claim 1, it is a formula 2aCompound,

Or its pharmacy acceptable salt, wherein R ²And R ¹³Has defined implication in the claim 1.

5. the compound of claim 1, it is a formula 2bCompound,

Or its pharmacy acceptable salt, wherein R ², R ¹²And R ¹³Has defined implication in the claim 1.

6. the compound of claim 1, it is a formula 3aCompound,

7. the compound of claim 1, it is a formula 3bCompound,

8. the compound of claim 1, it is a formula 4aCompound,

9. the compound of claim 1, it is a formula 4bCompound,

10. compound, it is selected from the group of being made up of following compound:

Or its pharmacy acceptable salt.

11. a pharmaceutical composition, it comprises the compound and the pharmaceutically acceptable carrier of claim 1.

12. the compound of claim 1 is used for treating the purposes in the medicine of Mammals abnormal cell growth in preparation.

13. the compound of following formula,

Or its pharmacy acceptable salt.

14. a pharmaceutical composition, it comprises the compound and the pharmaceutically acceptable carrier of claim 13.